Pyrazolopyrimidine derivatives as BTK inhibitors for the treatment of cancer

ABSTRACT

This invention relates to novel compounds. The compounds of the invention are tyrosine kinase inhibitors. Specifically, the compounds of the invention are useful as inhibitors of Bruton&#39;s tyrosine kinase (BTK). The invention also contemplates the use of the compounds for treating conditions treatable by the inhibition of Bruton&#39;s tyrosine kinase, for example cancer, lymphoma, leukemia and immunological diseases.

This application is a National Stage application under 35 U.S.C. § 371of International Application No. PCT/GB2016/052897, filed Sep. 16, 2016,which claims the benefit of priority to GB 1613947.9, filed Aug. 15,2016, GB 1522246.6, filed Dec. 16, 2015 and GB 1516445.2, filed Sep. 16,2015.

This invention relates to compounds. More specifically, the inventionrelates to compounds useful as kinase inhibitors, along with processesto prepare the compounds and uses of the compounds. Specifically, theinvention relates to inhibitors of Bruton's tyrosine kinase (BTK).

BACKGROUND

Kinases are a class of enzyme that control the transfer of phosphategroups from phosphate donor groups, for example ATP, to specificsubstrates. Protein kinases are a large subset of kinases that play acentral role in the regulation of a wide variety of cellular signallingand processes and BTK is one such protein kinase.

BTK is a member of the src-related Tec family of cytoplasmic tyrosinekinases. BTK plays a key role in the B-cell receptor (BCR) signallingpathway of B-cells, which is required for the development, activationand survival of B-cells. BTK inhibitors have therefore been developedwith the aim of treating B-cell malignancies that are dependent on BCRsignalling, such as chronic lymphocytic leukemia (CLL) and non-Hodgkin'slymphoma (NHL) (Buggy 2012). BTK is also expressed in specific myeloidcells including, monocytes/macrophages, neutrophils and mast cells. Inthese myeloid cells, BTK has been indicated in the immune complexmediated activation of FcγR and FcεR, which is believed to contribute tothe pathogenesis of rheumatoid arthritis (RA) (Whang 2014). In addition,BTK is required for the maturation of osteoclast cells and so inhibitingBTK could prevent the bone erosion that is associated with RA. Thecritical role of BTK in both B-cells and myeloid cells has led to BTKbecoming an attractive target for the treatment of not only B-cellmalignancies but also for the treatment of autoimmune diseases.

Ibrutinib is an irreversible BTK inhibitor that has been approved forthe treatment of CLL, mantle cell lymphoma (MCL) and Waldenstrom'smacroglobulinemia (WM). Since Ibrutinib was first disclosed there havebeen a number of patent applications concerned with structures closelyrelated to Ibrutinib, for example see WO 2012/158843, WO 2012/158764, WO2011/153514, WO 2011/046964, US 2010/0254905, US 2010/0144705, U.S. Pat.No. 7,718,662, WO, 2008/054827 and WO 2008/121742.

Further Btk inhibitors are disclosed in WO 2013/010136, U.S. Pat. No.9,090,621, WO 2015/127310, WO 2015/095099 and US 2014/221333. Kinaseinhibitors are also disclosed in U.S. Pat. No. 6,660,744, US2002/0156081, US 2003/0225098 and WO 01/19829.

Ibrutinib also irreversibly binds to interleukin-2 inducible tyrosinekinase (ITK) (Dubovsky 2013). ITK plays a critical role inFcR-stimulated natural killer (NK) cell function that is required forantibody dependent NK cell mediated cytotoxicity (ADCC). ADCC is themechanism that anti-CD20 antibodies, such as rituximab are believed toactivate and ibrutinib has been shown to antagonise this mechanism invitro (Kohrt 2014). As rituximab-combination chemotherapy is today'sstandard of care in B-cell malignancies, it would be desirable to have aBTK inhibitor with high selectivity for BTK over ITK.

In the clinic, adverse events have included atrial fibrillation,diarrhea, rash, arthralgia and bleeding (IMBRUVICA package insert 2014).Known BTK inhibitors, e.g. ibrutinib are also known to havegastrointestinal side effects, which are considered to be as a result ofa secondary EGFR inhibitory activity. It is therefore desirable to havea BTK inhibitor with high BTK inhibition and low EGFR inhibition toreduce or avoid the gastrointestinal side effects.

Irreversible and covalent reversible BTK inhibitors specifically targeta cysteine residue C481 within BTK. Following treatment with ibrutinib,cases of primary and secondary resistance have emerged. Mutations withinBTK such as C481S, C481Y, C481R, C481F have been reported in theliterature and clearly interfere with drug binding (Woyach 2014;Maddocks 2015). It has been predicted that the incidence of observedresistance will increase as clinical use outside clinical trials expandsover time (Zhang 2015).

Therefore, an aim of the present invention is to provide BTK inhibitorswith a different binding mode more specifically reversible inhibitors.In addition the invention aims to provide BTK inhibitors with highselectivity for BTK inhibition over EGFR and ITK inhibition.

Furthermore, it is an aim of certain embodiments of this invention toprovide new cancer treatments. In particular, it is an aim of certainembodiments of this invention to provide compounds which have comparableactivity to existing cancer treatments but are also effective againstmutations. One of the aspects of the invention focus on providing BTKinhibitors effective against the C481 mutations.

It is an aim of certain embodiments of this invention to providecompounds which exhibit reduced cytotoxicity relative to prior artcompounds and existing therapies.

Another aim of certain embodiments of this invention is to providecompounds having a convenient pharmacokinetic profile and a suitableduration of action following dosing. A further aim of certainembodiments of this invention is to provide compounds in which themetabolised fragment or fragments of the drug after absorption are GRAS(Generally Regarded As Safe).

Certain embodiments of the present invention satisfy some or all of theabove aims.

SUMMARY OF THE DISCLOSURE

In accordance with the present invention there is provided compounds asdisclosed below. Furthermore, the invention provides compounds capableof inhibiting Bruton's tyrosine kinase (BTK) and the use of thesecompounds in inhibiting BTK. In accordance with the invention there isprovided a method of treating conditions modulated by BTK. The inventionprovides compounds for use in treating a condition which is modulated byBTK.

In a first aspect of the invention there is provided a compoundaccording to formula (I) or pharmaceutically acceptable salts thereof:

whereinA represents a ring selected from substituted or unsubstituted: phenyl,pyridyl, pyridazine, pyrimidine, or pyrazine, wherein when substituted Acontains from 1 to 4 substitutents independently selected at eachoccurrence from: H, halo, C₁₋₆ alkyl, C₁₋₆ alkyl substituted with—OR^(a), C₁₋₆ haloalkyl, —OR^(a), C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl, C₃₋₈ cycloalkenyl, NR^(a)R^(b), —CN, acyl, —C(O)R^(a),—C(O)OR^(a), —SO₂R^(a), and —SO₃R^(a);D is selected from substituted or unsubstituted: C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, C₃₋₁₀ cycloalkenyl, C₆₋₁₀ aryl, 3 to 10 memberedheterocycloalkyl, 3 to 10 membered heterocycloalkenyl and 5 to 10membered heteroaryl, wherein, when substituted, D contains from 1 to 9substituents independently selected at each occurrence from: halo,—OR^(c), —NR^(c)R^(d), ═O, —CN, —C(O)OR^(c), —OC(O)R^(e),—C(O)NR^(c)R^(d), —NR^(c)C(O)R^(e), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkyl substituted with —OR^(c), C₃₋₈ cycloalkyl, —SO₂R^(c), SO₃R^(c),C(O)R^(c) and a 3 to 8 membered heterocyclic group;one of X and Y is N and the other is C, wherein

represents a single or double bond and a single bond is present betweenN and X or Y when X or Y is N and a double bond is present between N andX or Y when X or Y is C;n is selected from 1 or 2;R¹ is a group selected from a substituted or unsubstituted: C₃₋₈cycloalkyl, C₃₋₈ heterocycloalkyl, C₃₋₈ cycloalkenyl, C₃₋₈heterocycloalkenyl, aryl or heteroaryl moiety, wherein the aryl orheteroaryl moiety either contains 5 or 6 atoms in a single ring or from7 to 14 atoms in a fused polycyclic ring system, wherein, whensubstituted, R¹ contains from 1 to 9 substituents (optionally 1 to 5)independently selected at each occurrence from the group comprising:halo, —OR^(f), —NR^(f)R^(g), ═O, —CN, acyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkyl substituted with —OR^(f), C₁₋₆ alkyl substituted with C₃₋₈cycloalkyl, C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl, —SO₂R^(f), SO₃R^(f),—C(O)R^(f), —C(O)OR^(f), —C(O)NR^(f)R^(g), aryl optionally substitutedby 1 or 2 halo atoms, and 6 membered heteroaryl;R² is selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, andC₃₋₇ halocycloalkyl;R³ and R⁴ are independently selected at each occurrence from: H, halo,C₁₋₄ alkyl, C₁₋₄ alkyl substituted with —OR^(h), C₁₋₄ haloalkyl,—OR^(h), C₃₋₆ cycloalkyl and C₃₋₇ halocycloalkyl, or R³ and R⁴ takentogether with the atom on which they are substituted, form a 3 to 6membered cycloalkyl ring;R⁵ and R⁶ are independently selected at each occurrence from: H, C₁₋₄alkyl, C₁₋₄ alkyl substituted with —OR^(h), C₁₋₄ haloalkyl, C₁₋₄ acyl,C₃₋₇ cycloalkyl, and C₃₋₇ halocycloalkyl;R^(a) and R^(h) are independently selected at each occurrence from: H,C₁₋₄ alkyl, C₁₋₄ alkyl substituted with —OR^(i), C₁₋₄ haloalkyl, acyl,C₃₋₇ cycloalkyl, and C₃₋₇ halocycloalkyl;R^(c), R^(d) and R^(e) are independently selected at each occurrencefrom: H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkyl substituted with —OR,unsubstituted aryl, aryl substituted with halo or C₁₋₄ alkyl or C₁₋₄haloalkyl or a combination thereof, C₃₋₇ cycloalkyl, and C₃₋₇halocycloalkyl;R^(f) and R^(g) are independently selected at each occurrence from: H,C₁₋₄ alkyl, C₁₋₄ alkyl substituted with —OR^(k), C₁₋₄ haloalkyl, acyl,C₃₋₇ cycloalkyl, and C₃₋₇ halocycloalkyl;R^(h), R^(i), R^(j), and R^(k) are independently selected at eachoccurrence from: H, C₁₋₄ alkyl, C₁₋₄ alkyl substituted with —OR^(l) andC₁₋₄ haloalkyl; andR^(l) is independently selected at each occurrence from: H, C₁₋₄ alkyl,and C₁₋₄ haloalkyl.

In embodiments R¹ contains 1 to 9 substituents (optionally 1 to 5). Atleast one of the substituents and the —C(═O)— (which is bonded to R¹)are bonded to adjacent carbon atoms of R¹. In other words thesubstituent and —C(═O) are ortho substituted.

In embodiments R¹ is a group selected from a substituted orunsubstituted: C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl, C₃₋₈cycloalkenyl, C₃₋₈ heterocycloalkenyl, aryl or heteroaryl moiety,wherein the aryl or heteroaryl moiety either contains 5 or 6 atoms in asingle ring or from 7 to 14 atoms in a fused polycyclic ring system,wherein, when substituted, R¹ contains from 1 to 9 substituentsindependently selected at each occurrence from the group disclosedabove. Thus, it is evident that R¹ can be a single ring or a fusedpolycylic (optionally bicyclic ring system) with from 1 to 9substituents. As discussed in the immediately preceding pargagraph (andas evident to the skilled person from the structure of formula (I)) a—C(═O)— group is bonded to R¹. Preferably, R¹ comprises an acceptorfunction ortho to the —C(═O)— group. The acceptor function may be ahydrogen bond acceptor. The ortho acceptor function may be a heteroatomwithin R¹ (for example, within a ring which is attached to —C(═O)— orwithin a ring fused to the ring attached to —C(═O)—) or a substituent onR¹.

Where the group R¹ is a polycyclic ring system it may be fully orpartially aromatic, i.e. one ring is aromatic and the other(s) are not.

In cases where more than one substituent is possible on a carbon atom,two substituents on the same carbon may form a ring system, e.g. aspirocyclic system. An example of this type of spiro substitution is theformation of a ketal from a ketone and a diol. For example, the 3 to 8membered heterocyclic group that may be a substituent on D may besubstituted so as to form a spirocycle. Therefore, D may be:

In embodiments R² is selected from H, C₁₋₄ alkyl, C₁₋₄ acyl, and C₃₋₇cycloalkyl. Preferably R² is H or C₁₋₄ alkyl (e.g. methyl). Mostpreferably R² is H.

Accordingly, in a preferred embodiment the compound of formula (I) maybe a compound according to formula (II):

In an embodiment R³ and R⁴ are independently selected at each occurrencefrom: H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkyl substituted with—OR^(h), —OR^(h), or R³ and R⁴ taken together with the atom on whichthey are substituted, form a 3 to 6 membered cycloalkyl ring.Preferably, R³ and R⁴ are independently selected at each occurrencefrom: H, halo (e.g. fluoro and chloro), C₁₋₄ alkyl (e.g. methyl orethyl), C₁₋₄ haloalkyl (e.g. trifluoromethyl or trifluoroethyl), —OR^(h)(e.g. methoxy, ethoxy and OCF₃), C₁₋₄ alkyl substituted with —OR^(h)(e.g. —CH₂OH) or R³ and R⁴ taken together with the atom on which theyare substituted form a cyclopropyl ring. Further preferably R³ and R⁴are H or methyl. Accordingly, R³ and R⁴ may be H for compounds of anyformulae of the present invention.

In an embodiment R³ is H and R⁴ is as defined elsewhere herein.

Preferably n is 1.

In an embodiment, R⁵ and R⁶ are hydrogen, C₁₋₄ alkyl, or C₁₋₄ alkylsubstituted with —OR^(h), preferably H, methyl or —(CH₂)₂OMe (optionallyH or —(CH₂)₂OMe). R⁵ may be H and R⁶ may be as defined elsewhere herein.In an embodiment, R⁵ is H and R⁶ is hydrogen, C₁₋₄ alkyl, or C₁₋₄ alkylsubstituted with —OR^(h). Preferably, R⁵ is H and R⁶ is H, methyl or—(CH₂)₂OMe (optionally H or —(CH₂)₂OMe). R⁵ and R⁶ may both be hydrogen.

In a preferred embodiment, the compound of formula (I) may be a compoundaccording to formulae (IIIa) or (IIIb):

In embodiments X is N and Y is C thus

represents a single bond between N and X and a double bond between N andY. Therefore, the compound of formula (I) may be a compound according toformula (IV):

In a preferred embodiment, there is provided a compound of formula (IV)wherein R³ and R⁴ are H, and R⁵ and R⁶ are H. In a preferred embodiment,there is provided a compound of formula (IV), wherein A is unsubstitutedor substituted phenyl or pyridyl (preferably unsubstituted phenyl orfluorophenyl), R³ and R⁴ are H, and R⁵ and R⁶ are H. In an embodiment,there is provided a compound of formula (IV), wherein A is substitutedor unsubstituted fluorophenyl, phenyl or pyridyl (preferablyunsubstituted phenyl or fluorophenyl), R³ and R⁴ are H, R⁵ and R⁶ are H,and R¹ is substituted or unsubstituted phenyl (preferably substitutedphenyl). R¹ may be phenyl substituted with 1, 2 or 3 groups selectedfrom: methoxy, fluoro, —OCF₃, OEt, O^(i)Pr, Cl, Me, CF₃, or CN(preferably R¹ is methoxyphenyl). R¹ may be phenyl substituted at thetwo position. In other words R¹ may be ortho substituted. Preferably, R¹is 2-methoxyphenyl.

In embodiments X is C and Y is N thus

represents a single bond between N and Y and a double bond between N andX. Therefore, the compound of formula (I) may be a compound according toformula (V):

In a preferred embodiment, there is provided a compound of formula (V)wherein R³ and R⁴ are H, and R⁵ and R⁶ are H. In a preferred embodiment,there is provided a compound of formula (V), wherein A is unsubstitutedor substituted phenyl or pyridyl (preferably unsubstituted phenyl orfluorophenyl), R³ and R⁴ are H, and R⁵ and R⁶ are H. In an embodiment,there is provided a compound of formula (V), wherein A is substituted orunsubstituted fluorophenyl, phenyl or pyridyl (preferably unsubstitutedphenyl or fluorophenyl), R³ and R⁴ are H, R⁵ and R⁶ are H, and R¹ issubstituted or unsubstituted phenyl (preferably substituted phenyl). R¹may be phenyl substituted with 1, 2 or 3 groups selected from: methoxy,fluoro, —OCF₃, OEt, O^(i)Pr, Cl, Me, CF₃, or CN (preferably R¹ ismethoxyphenyl). R¹ may be phenyl substituted at the two position. Inother words R¹ may be ortho substituted. Preferably, R¹ is2-methoxyphenyl.

In embodiments A is substituted or unsubstituted: phenyl or pyridyl.Preferably, A is substituted or unsubstituted phenyl.

A may be substituted or unsubstituted when substituted A may besubstituted by 1, 2 or 3 (preferably 1) substituent selected from: H,halo, C₁₋₆ alkyl, C₁₋₆ alkyl substituted with —OR^(a), C₁₋₆ haloalkyl,—OR^(a), NR^(a)R^(b), or —CN.

When substituted, A may be substituted by: H, halo, e.g. fluoro orchloro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or —OR^(a). In particular A may besubstituted with: H, fluoro, chloro, Me, OMe or CF₃.

Optionally, A is phenyl, pyridyl, fluorophenyl, difluorophenyl,methylphenyl or methoxyphenyl. A may be pyridyl, difluorophenyl,methylphenyl, methoxyphenyl, fluorophenyl or phenyl. Preferably, A ispyridyl, fluorophenyl or phenyl. Preferably, A is fluorophenyl orphenyl.

R^(a) and R^(b) may be selected from C₁₋₄ alkyl, C₁₋₄ alkyl substitutedwith —OR^(i), or C₁₋₄ haloalkyl. In particular R^(a) and R^(b) may be H,methyl, ethyl, —CH₂OR^(i), —(CH₂)₂OR^(i), —CF₃, —CHF₂, or —CH₂CF₃. R^(i)may be H, methyl or ethyl.

As the skilled person will appreciate from the definition of A, A is a 6membered ring. A may be unsubstituted (except for the 2 groups shown inFormula (I)) or substituted by 1 to 4 further substitutents as definedelsewhere herein. Thus, other than these 1 to 4 further substitutents Ais always substituted by

to form the compounds of formula (I), i.e. the compounds of theinvention, and these two groups may be substituted at any (chemicallypossible) positions on the 6 membered ring of A. In other words, thepoints of attachment of these two groups on ring A may be varied. Thus,the substitution may be ortho, meta or para. Preferably the substitutionis meta or para, most preferably para.

In some embodiments A is an optionally further substituted: phenyl,pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring with the furthersubstituents being independently selected from fluoro, methyl or methoxyand the two groups

may be substituted meta or para to one another on A.

A may be phenyl, fluorophenyl, methoxyphenyl, methylphenyl, pyridyl,pyrimidinyl, pyrazinyl or pyridazinyl and the two groups

are substituted para to one another on A.

Preferably, A is phenyl or fluorophenyl and the two groups aresubstituted para to one another. Accordingly the compound of formula (I)may be a compound according to formulae (VIa) or (VIb):

The compound of formula (I) may be a compound according to formulae(VIc) or (VId):

In an embodiment there is provided a compound of formulae (VIa) or (VIb)wherein R² is H. In a preferred embodiment, there is provided a compoundof formulae (VIa) or (VIb) wherein R³ and R⁴ are H, and R⁵ and R⁶ are H.In a particularly preferred embodiment, there is provided a compound offormulae (VIa) or (VIb) wherein R² is H, R³ and R⁴ are H, and R⁵ and R⁶are H. In a preferred embodiment, there is provided a compound offormulae (VIa) or (VIb), wherein A is unsubstituted or substitutedfluorophenyl, phenyl or pyridyl (preferably unsubstituted phenyl orfluorophenyl), R³ and R⁴ are H, and R⁵ and R⁶ are H. In an embodiment,there is provided a compound of formulae (VIa) or (VIb), wherein A issubstituted or unsubstituted phenyl or pyridyl (preferably unsubstitutedphenyl or fluorophenyl), R³ and R⁴ are H, R⁵ and R⁶ are H, and R¹ issubstituted or unsubstituted phenyl (preferably substituted phenyl). R¹may be phenyl substituted with 1, 2 or 3 groups selected from: methoxy,fluoro, —OCF₃, OEt, O^(i)Pr, Cl, Me, CF₃, or CN (preferably R¹ ismethoxyphenyl). R¹ may be phenyl substituted at the two position. Inother words R¹ may be ortho substituted. Preferably, R¹ is2-methoxyphenyl.

In an embodiment there is provided a compound formulae (VIc) or (VId)wherein R² is H. In a preferred embodiment, there is provided a compoundof formulae (VIc) or (VId) wherein R³ and R⁴ are H, and R⁵ and R⁶ are H.In a particularly preferred embodiment, there is provided a compound offormulae (VIc) or (VId) wherein R² is H, R³ and R⁴ are H, and R⁵ and R⁶are H. In a preferred embodiment, there is provided a compound offormulae (VIc) or (VId), wherein R³ and R⁴ are H, and R⁵ and R⁶ are H.In an embodiment, there is provided a compound of formulae (VIc) or(VId), wherein R³ and R⁴ are H, R⁵ and R⁶ are H, and R¹ is substitutedor unsubstituted phenyl (preferably substituted phenyl). R¹ may bephenyl substituted with 1, 2 or 3 groups selected from: methoxy, fluoro,—OCF₃, OEt, O^(i)Pr, Cl, Me, CF₃, or CN (preferably R¹ ismethoxyphenyl). R¹ may be phenyl substituted at the two position. Inother words R¹ may be ortho substituted. Preferably, R¹ is2-methoxyphenyl.

The group R¹ may be a substituted or unsubstituted: C₃₋₈ cycloalkyl,C₃₋₈ heterocycloalkyl, C₃₋₈ cycloalkenyl, or C₃₋₈ heterocycloalkenyl.Optionally, R¹ is a substituted or unsubstituted: C₅₋₆ cycloalkyl, C₅₋₆heterocycloalkyl, C₅₋₆ cycloalkenyl, or C₅₋₆ heterocycloalkenyl.

The group R¹ may be a substituted or unsubstituted: aryl or heteroarylmoiety which either contains 5 or 6 atoms in a single ring. Optionally,R¹ is a substituted or unsubstituted: aryl or heteroaryl moiety whichcontains 6 atoms in a single ring.

The group R¹ may be a substituted or unsubstituted: aryl or heteroarylmoiety which contains from 7 to 14 atoms in a fused polycyclic ringsystem.

For the avoidance of doubt, when R¹ is a fused polycyclic system, fusioncan occur at any point on the two or more fused rings. Furthermore, thefused polycyclic system can be a 6,6- or 6,5-fused ring system.

In an embodiment R¹ is a substituted or unsubstituted: aryl orheteroaryl moiety which contains 6 atoms in a single ring or from 7 to14 atoms in a fused polycyclic ring system, wherein one of thesubstituents on the single ring and the —C(═O)— are bonded to adjacentcarbon atoms of R¹ and the —C(═O)— group is substituted on the fusedpolycyclic ring system ortho to one of the two points of fusion of thepolycyclic system.

The group R¹ may be a substituted or unsubstituted: C₃₋₈ cycloalkyl(optionally C₃₋₆, or C₅₋₆ cycloalkyl), C₃₋₈ heterocycloalkyl (optionallyC₃₋₆ or C₅₋₆ heterocycloalkyl), C₆₋₁₄ aryl (optionally C₆ C₉, or C₁₀aryl) or C₅₋₁₄ heteroaryl (optionally C₅, C₆ or C₁₀ heteroaryl). Whensubstituted, R¹ may contain 1, 2 or 3 substituents independentlyselected at each occurrence from the group comprising: halo, —OR^(f),—NR^(f)R^(g), ═O, —CN, acyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkylsubstituted with —OR^(f), C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl,—SO₂R^(f), SO₃R^(f), —C(O)R^(f), —C(O)OR^(f), —C(O)NR^(f)R^(g) and aryloptionally substituted by 1 or 2 halo atoms.

In embodiments R¹ may be substituted or unsubstituted 6 membered aryl or6 membered heteroaryl, optionally unsubstituted phenyl, unsubstitutedpyridyl, substituted pyridyl or substituted phenyl.

In embodiments R¹ may be substituted or unsubstituted: 9, 10 or 11membered aryl or heteroaryl in a fused polycyclic system. Thus, R¹ maybe substituted or unsubstituted: indene, indane, naphthalene, tetralin,indole, isoindole, indoline, isoindoline, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, indazole, benzimidazole,benzothiazole, benzopyrazole, benzopyrole, benzoxazole,isobenzothiazole, isobenzoxazole, benzomorpholine, benzothiomorpholine,purine, quinoline, isoquinoline, chromene, chromane, isochromane,cinnoline, quinazoline, quinoxaline, napthyridine, pthalazine, orpteridine.

R¹ may be selected from unsubstituted or substituted: cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl,cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene,cyclooctenyl or cycloatadienyl.

R¹ may be selected from unsubstituted or substituted: oxirane,aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, pyroline,imidazolidine, imidazoline, succinimide, pyrazolidine, pyrazoline,oxazolidine, oxazoline, dioxolane, isoxazolidine, isoxazoline,thiazolidine, thiazoline, isothiazolidine, isothiazoline, piperidine,morpholine, thiomorpholine, piperazine, dioxane, dihydropyran, ortetrahydropyran.

R¹ may be selected from unsubstituted or substituted: cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl,cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene,cyclooctenyl, cycloatadienyl, oxirane, aziridine, azetidine, oxetane,tetrahydrofuran, pyrrolidine, pyroline, imidazolidine, imidazoline,succinimide, pyrazolidine, pyrazoline, oxazolidine, oxazoline,dioxolane, isoxazolidine, isoxazoline, thiazolidine, thiazoline,isothiazolidine, isothiazoline, piperidine, morpholine, thiomorpholine,piperazine, dioxane, dihydropyran, tetrahydropyran, phenyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, indene, indane, naphthalene,tetralin, indole, isoindole, indoline, isoindoline, benzofuran,isobenzofuran, benzothiophene, isobenzothiophene, indazole,benzimidazole, benzothiazole, benzoxazole, isobenzothiazole,isobenzoxazole, benzopyrazole, benzopyrole, benzomorpholine,benzothiomorpholine, purine, quinoline, isoquinoline, chromene,chromane, isochromane, cinnoline, quinazoline, quinoxaline,napthyridine, pthalazine, or pteridine.

R¹ may be substituted or unsubstituted: phenyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, indene, indane, naphthalene, tetralin, indole,isoindole, indoline, isoindoline, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, indazole, benzimidazole,benzothiazole, benzoxazole, purine, quinoline, isoquinoline, chromene,chromane, isochromane, cinnoline, quinazoline, quinoxaline,napthyridine, pthalazine, or pteridine.

The R¹ group is bonded to the rest of the compound by a —C(═O)— group.Optionally, when R¹ is a fused polycyclic ring system the —C(═O)— groupis substituted ortho to one of the two points of fusion of thepolycyclic system. For example, R¹ may be a naphthalene, quinoline,chromane or benzomorpholine ring and the point of fusion ortho to theposition of attachment of the —C(═O)— group is as shown below:

In an embodiment when R¹ is a fused polycyclic ring system, the —C(═O)—group is substituted ortho to one of two points of fusion of thepolycyclic system. The point of fusion is a carbon atom with a bond(within one of the fused rings) to an acceptor function, which may be anO, N or S atom. These groups can be represented as follows:

Alternatively, the —C(═O)— group is substituted ortho to a heteroatomwithin the fused bicycic system. For example R¹ may be a quinoline,chromane, benzomorpholine, indole, benzofuran, benzothiophene,benzoxazole, or benzothiazole ring where the —C(═O)— group issubstituted ortho to one point of fusion and the point of fusion is acarbon atom with a bond to an acceptor function can be represented asfollows:

For the avoidance of doubt the fused bicyclic system described in theabove two paragraphs may be substituted as described elsewhere herein.For example, the fused systems may be substituted by a substituent orthoto the —C(═O)— group.

Optionally, when R¹ is substituted it is substituted by 1, 2 or 3substituents independently selected at each occurrence from the groupcomprising: halo, —OR^(f), —CN, ═O, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkyl substituted with —OR^(f), C₁₋₆ alkyl substituted with cycloalkyl,optionally wherein R^(f) is selected from H, C₁₋₄ alkyl and C₁₋₄haloalkyl. Preferably the substituents are independently selected fromfluoro, chloro, methoxy, ethoxy, isopropoxy, —CN, methyl, ethyl,trifluoromethyl, trifluoroethyl or —OCF₃.

R^(f) and R^(g) may be selected from H, C₁₋₄ alkyl and C₁₋₄ haloalkyl,optionally H, methyl, ethyl, —CF₃, or —CF₂H.

In embodiments R¹ may be unsubstituted phenyl, unsubstituted pyridyl,substituted phenyl or substituted pyridyl and when substituted R¹ issubstituted with 1, 2 or 3 substituents independently selected at eachoccurrence from the group comprising: halo, —OR^(h), —CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, wherein R^(h) is selected from H, C₁₋₄ alkyl and C₁₋₄haloalkyl. Preferably the substituents are independently selected fromfluoro, chloro, methoxy, ethoxy, isopropoxy, —CN, methyl, ethyl,trifluoromethyl, trifluoroethyl or —OCF₃.

In embodiments R¹ is selected from: phenyl, fluorophenyl,difluorophenyl, chlorophenyl, methylphenyl (also referred to as tolyl),methoxyphenyl, ethoxyphenyl, isopropoxyphenyl, trifluromethylphenyl,cyanophenyl, trifluoromethoxyphenyl, tert-butylphenyl,methyl-fluorophenyl (also referred to as fluorotolyl),fluoro-methoxyphenyl, fluoro-trifluoromethylphenyl,fluoro-trifluoromethoxyphenyl, chloro-methoxyphenyl,methoxy-methylphenyl (also referred to as methoxytolyl),methoxy-trifluoromethylphenyl, chloro-trifluoromethylphenyl,ethoxy-trifluoromethylphenyl, dimethoxyphenyl,di(trifluoromethyl)phenyl, trifluorophenyl, chloro-methylphenyl (alsoreferred to as chorotolyl), pyridyl, fluoropyridyl, difluoropyridyl,chloropyridyl, methylpyridyl (also referred to as picoline),methoxypyridyl, ethoxypyridyl, isopropoxypyridyl, trifluromethylpyridyl,cyanopyridyl, trifluoromethoxypyridyl, tert-butylpyridyl,methyl-fluoropyridyl (also referred to as fluoropicoline),fluoro-methoxypyridyl, fluoro-trifluoromethylpyridyl,fluoro-trifluoromethoxypyridyl, chloro-methoxypyridyl,methoxy-methylpyridyl (also referred to as methoxypicoline),methoxy-trifluoromethylpyridyl, chloro-trifluoromethylpyridyl,ethoxy-trifluoromethylpyridyl, dimethoxypyridyl,di(trifluoromethyl)pyridyl, trifluoropyridyl and chloro-methylpyridyl(also referred to as choropicoline).

Accordingly, in embodiments the compound of formula (I) may be acompound according to formulae (VIIa) or (VIIb):

wherein zero, one or two B¹, B², B³, B⁴ and B⁵ is N and the remainingare independently selected from CH or CR⁷. Alternatively, two of B¹, B²,B³, B⁴ and B⁵ which are adjacent to each other are C and together form afurther five or six membered ring which is fused to the ring representedby B¹, B², B³, B⁴ and B⁵ to form a bicyclic ring system. This further 5or 6 membered ring may be selected from a: aryl, heteroaryl,heterocycloalkyl, cycloalkyl, heterocycloalkenyl or cycloalkenyl ring,and zero, one or two B¹, B², B³ and B⁴ is N and the remaining areindependently selected from CH or CR⁷.

R⁷ is independently selected at each occurrence from: H, halo, —OR^(f),—NR^(f)R^(g), ═O, —CN, acyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkylsubstituted with —OR^(f), C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl,—SO₂R^(f), SO₃R^(f), —C(O)R^(f), —C(O)OR^(f), —C(O)NR^(f)R^(g) and aryloptionally substituted by 1 or 2 halo atoms.

In an embodiment B¹ is N or CR⁷ (optionally R⁷ is —OR^(f), preferably—OMe) and either two adjacent B², B³, B⁴ and B⁵ are C and together forma further 5 or 6 membered ring which is fused to the ring represented byB², B³, B⁴ and B⁵ to form a bicyclic ring system, wherein the further 5or 6 membered ring may be selected from a: aryl, heteroaryl,heterocycloalkyl, cycloalkyl, heterocycloalkenyl or cycloalkenyl ring,and the remainder of B², B³, B⁴ and B⁵ are independently selected fromCH or CR⁷, or B², B³, B⁴ and B⁵ are independently selected from CH orCR⁷.

In an embodiment B¹ is N or CR⁷ (optionally R⁷ is —OR^(f), preferably—OMe), B⁴ and B⁵ are C and together form a further 5 or 6 membered ringwhich is fused to the ring represented by B², B³, B⁴ and B⁵ to form abicyclic ring system, wherein the further 5 or 6 membered ring may beselected from a: aryl, heteroaryl, heterocycloalkyl, cycloalkyl,heterocycloalkenyl or cycloalkenyl ring, and B² and B³ are CH.

As discussed above the substituent on R¹ and —(C═O)— may be bonded toadjacent carbon atoms of R¹. In other words the substituent and —(C═O)—are ortho substituted. The substituent may be R⁷. Hence, R⁷ and —(C═O)—may be ortho substituted. Accordingly, in embodiments the compound offormula (I) may be a compound according to formulae (VIIc) or (VIId):

wherein zero, one or two B¹, B², B³ and B⁴ is N and the remaining areindependently selected from CH or CR⁷. Alternatively, two of B¹, B², B³and B⁴ which are adjacent to each other together form a further five orsix membered ring which is fused to the ring represented by B¹, B², B³and B⁴ to form a bicyclic ring system. This further 5 or 6 membered ringmay be selected from a: aryl, heteroaryl, heterocycloalkyl, cycloalkyl,heterocycloalkenyl or cycloalkenyl ring, and zero, one or two B¹, B², B³and B⁴ is N and the remaining are independently selected from CH or CR⁷.R⁷ is independently selected at each occurrence from: H, halo, —OR^(f),—NR^(f)R^(g), ═O, —CN, acyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkylsubstituted with —OR^(f), C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl,—SO₂R^(f), SO₃R^(f), —C(O)R^(f), —C(O)OR^(f), —C(O)NR^(f)R^(g) and aryloptionally substituted by 1 or 2 halo atoms.

Optionally, B¹ and B² form the further five or six membered ring.Further optionally, B¹ is N, CH or CR⁷ and B², B³ and Ware independentlyselected from CH or CR⁷ or two adjacent B², B³ and B⁴ groups togetherform a five or six membered aryl, heteroaryl, heterocycloalkyl,cycloalkyl, heterocycloalkenyl or cycloalkenyl ring,

In embodiments, R⁷ is —OR^(f), preferably —OMe, and B¹, B², B³ and B⁴ isCH or two adjacent atoms form a further 5 or 6 membered ring which isfused to the ring represented by B¹, B², B³ and B⁴ to form a bicyclicring system, wherein the further 5 or 6 membered ring may be selectedfrom a: aryl, heteroaryl, heterocycloalkyl, cycloalkyl,heterocycloalkenyl or cycloalkenyl ring. Preferably, the further 5 or 6membered ring is a phenyl or pyridyl ring. In embodiments, R⁷ is H, B¹is N and B², B³ and B⁴ is CH or two of B², B³ and B⁴ which are adjacentare C atoms and together form a further 5 or 6 membered ring which isfused to the ring represented by B², B³, B⁴ and B⁵ to form a bicyclicring system, wherein the further 5 or 6 membered ring may be selectedfrom a: aryl, heteroaryl, heterocycloalkyl, cycloalkyl,heterocycloalkenyl or cycloalkenyl ring. Preferably the further ring isa phenyl ring. In embodiments, R⁷ is H or —OR^(f), preferably H or —OMe,B¹ and B² are C and together form a pyridine ring, preferably whereinthe N atom of the pyridine ring is attached to B¹.

R⁷ may be independently selected at each occurrence from the groupcomprising: H, halo, —OR^(f), —CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkyl substituted with —OR^(f), optionally wherein R^(f) is selectedfrom H, C₁₋₄ alkyl and C₁₋₄ haloalkyl. Preferably, R⁷ is independentlyselected from fluoro, chloro, methoxy, ethoxy, isopropoxy, —CN, methyl,ethyl, trifluoromethyl, trifluoroethyl or —OCF₃ (optionally methoxy).

As discussed above, when R¹ is a fused polycyclic ring system the—C(═O)— group may be substituted ortho to one of the two points offusion of the polycyclic system. Accordingly, in embodiments thecompound of formula (I) may be a compound according to formulae (VIIIa)or (VIIIb):

wherein ring B and ring C represent an independently selectedsubstituted or unsubstituted 5 or 6 membered: aryl, heteroaryl,cycloalkyl, cycloalkylene, heterocycloalkyl or heterocycloalkylene ringswherein at least one of ring B or ring C is an aryl or heteroaryl ring;andZ is CR⁷, O, N, S or NH.

As discussed above where R¹ is a fused polycyclic ring system the—C(═O)— group may be substituted ortho to one of two points of fusion ofthe polycyclic system and the point of fusion may be a carbon atom witha bond (within one of the fused rings) to an acceptor function, whichmay be an O, N or S atom. Accordingly, in embodiments the compound offormula (I) may be a compound according to formulae (IXa) or (IXb):

wherein ring B¹ represents a substituted or unsubstituted 5 or 6membered: aryl, heteroaryl, cycloalkyl, cycloalkylene, heterocycloalkylor heterocycloalkylene ring;ring C¹ represents a heteroaryl, heterocycloalkyl or heterocycloalkylenering; andZ¹ is O, N, S or NH;wherein at least one of ring B¹ or ring C¹ is an aryl or heteroarylring.

For the avoidance of doubt, rings B and C of formulae (VIIIa) and(VIIIb) and rings B¹ and C¹ of formulae (IXa) and (IXb) are fusedbicyclic ring systems.

Compounds of the invention where R¹ comprises an acceptor function orthoto the —C(═O)— group are particularly preferred. The acceptor functionbeing a hydrogen bond acceptor. The ortho acceptor function may bewithin a ring fused to the ring attached to —C(═O)—, a substituent onR¹, or within the ring which is attached to —C(═O)—. Without being boundby theory it is believed that the ortho acceptor function might improvepermeability of the compounds of the present invention. Therefore, incertain embodiments of the present invention it is an aim to improvepermeability.

In an embodiment there is provided a compound of formulae (VIIIa),(VIIIb), (IXa) and (IXb) wherein R² is H. In a preferred embodiment,there is provided a compound of formulae (VIIIa), (VIIIb), (IXa) and(IXb) wherein R³ and R⁴ are H, and R⁵ and R⁶ are H. In a particularlypreferred embodiment, there is provided a compound of formulae (VIIIa),(VIIIb), (IXa) and (IXb) wherein R² is H, R³ and R⁴ are H, and R⁵ and R⁶are H. In a preferred embodiment, there is provided a compound offormulae (VIIIa), (VIIIb), (IXa) and (IXb), wherein A is unsubstitutedor substituted phenyl or pyridyl (preferably unsubstituted phenyl orfluorophenyl), R³ and R⁴ are H, and R⁵ and R⁶ are H. In an embodiment,there is provided a compound of formulae (VIIIa), (VIIIb), (IXa) and(IXb), wherein A is substituted or unsubstituted phenyl or pyridyl(preferably unsubstituted phenyl or fluorophenyl), R³ and R⁴ are H, R⁵and R⁶ are H, and rings B, C, B¹ or C¹ are independently unsubstitutedor substituted with 1, 2 or 3 groups selected from: methoxy, fluoro,—OCF₃, OEt, O^(i)Pr, Cl, Me, CF₃, or CN (preferably methoxy).

In an embodiment, D is selected from substituted or unsubstituted: C₁₋₆alkyl, C₅₋₉ cycloalkyl, C₅₋₉ cycloalkenyl, C₆₋₁₀ aryl, 5 to 9 memberedheterocycloalkyl, 5 to 9 membered heterocycloalkenyl or 5, 6, 9 or 10membered heteroaryl.

In an embodiment, D is selected from substituted or unsubstituted: C₁₋₆alkyl, C₅₋₉ cycloalkyl, C₅₋₉ cycloalkenyl, C₆₋₁₀ aryl, 5 to 9 memberedheterocycloalkyl, 5 to 9 membered heterocycloalkenyl or 5, 6, 9 or 10membered heteroaryl.

D may be selected from substituted or unsubstituted: tert-butyl,cyclopentyl, cyclohexyl, bicyclohexyl, cyclopentenyl, cyclohexenyl,indanyl, tetrahydrofuran and tetrahydropyran. Preferably D may beunsubstituted or substituted: cyclopentyl, bicyclohexyl orcyclopentenyl. Alternatively, D may be substituted cyclopentyl,unsubstituted or substituted bicyclohexyl, or unsubstituted orsubstituted cyclopentenyl.

D may be selected from substituted or unsubstituted: tert-butyl,trifluoroethyl, cyclopentyl, cyclohexyl, bicyclohexyl, cyclopentenyl,cyclohexenyl, indanyl, tetrahydrofuran and tetrahydropyran. Preferably Dmay be unsubstituted or substituted: cyclopentyl, bicyclohexyl orcyclopentenyl. Alternatively, D may be trifluoroethyl, substitutedcyclopentyl, substituted cyclohexyl, unsubstituted or substitutedbicyclohexyl, or unsubstituted or substituted cyclopentenyl.

In a preferred embodiment D is tert-butyl or isopropyl.

In a preferred embodiment D is trifluoroethyl, tert-butyl or isopropyl.

D may be selected from substituted or unsubstituted: tert-butyl,isopropyl, 2-hydroxypropyl, cyclopentyl, cyclohexyl, bicyclohexyl,cyclopentenyl, cyclohexenyl, indanyl, tetrahydrofuran andtetrahydropyran. Preferably D may be unsubstituted or substituted:tert-butyl, isopropyl, 2-hydroxypropyl, cyclopentyl, bicyclohexyl orcyclopentenyl. Alternatively, D may be substituted cyclopentyl,unsubstituted or substituted bicyclohexyl, or unsubstituted orsubstituted tert-butyl, isopropyl, 2-hydroxypropyl, cyclopentenyl.

In a preferred embodiment D is tert-butyl, unsubstituted cyclopentyl,substituted cyclopentenyl, substituted cylopentenol, substitutedcyclohexanol, or trifluoroethyl.

D may be substituted or unsubstituted, when substituted D contains 1 to5 substituents independently selected at each occurrence from the groupcomprising: halo, —OR^(c), —NR^(c)R^(d), ═O, —CN, —C(O)OR^(c),—OC(O)R^(e), —C(O)NR^(c)R^(d), —NR^(c)C(O)R^(e), C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkyl substituted with —OR^(c), and a 3 to 8 memberedheterocyclic group. Optionally, the 3 to 8 membered heterocyclic groupis a 3 to 6 (e.g. a 5 or 6) membered heterocyclic group. Theheterocyclic group may be a heteroaryl group or a hetercycloalkyl group.

D may be substituted or unsubstituted, when substituted D contains 1 to5 substituents independently selected at each occurrence from the groupcomprising: chloro, fluoro, —OH, —OMe, —OEt, —O(CH₂)₂OMe, —NH₂, —NHMe,—NMe₂, ═O, —C(O)OH, —C(O)OMe, —C(O)OEt, —C(O)NH₂, —C(O)NHMe, —C(O)NMe₂,—OC(O)Me, —OC(O)Et, —OC(O)t-Bu, —OC(O)tolyl, —NHC(O)Me, —NHC(O)Me,—NHC(O)Et, —NHC(O)t-Bu, —NHC(O)tolyl, methyl, ethyl, iso-propyl,tert-butyl, triazole, tetrazole and dioxolane. The dioxolane substituentmay be substituted on D so as to form a spirocycle.

R^(c), R^(d) and R^(e) are independently selected at each occurrencefrom: H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkyl substituted with —OR,unsubstituted aryl and aryl substituted with halo or C₁₋₄ alkyl or C₁₋₄haloalkyl or a combination thereof.

In an embodiment R^(c) and R^(d) are independently selected at eachoccurrence from: H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₁₋₄ alkylsubstituted with —OR; and R^(e) is selected from: H, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkyl substituted with —OR, unsubstituted aryl and arylsubstituted with halo or C₁₋₄ alkyl or C₁₋₄ haloalkyl or a combinationthereof.

R^(h), R^(i), R^(j), R^(k), and R^(l) may be independently selected ateach occurrence from: H, C₁₋₄ alkyl and C₁₋₄ haloalkyl. R^(h), R^(i),R^(j), R^(k), and R^(l) are independently selected at each occurrencefrom: H, methyl, ethyl, —CF₃ or —CF₂H, preferably H or methyl.

In embodiments D is not unsubstituted cyclopentyl. In other words, whenD is cyclopentyl it is preferably substituted by 1, 2 or 3 substituentsas defined above for D. In embodiments where D is unsubstitutedcyclopentyl at least one of the substituents on R¹ and the —C(═O)— group(which is bonded to R¹) are bonded to adjacent carbon atoms of R¹. Inother words the substituent and —C(═O) are ortho substituted.

In embodiments there are provided compounds where:

D is selected from substituted or unsubstituted: C₁₋₆ alkyl, C₃₋₁₀cycloalkenyl, C₆₋₁₀ aryl, 3 to 10 membered heterocycloalkyl, 3 to 10membered heterocycloalkenyl and 5 to 10 membered heteroaryl, substitutedC₃₋₁₀ cycloalkyl, unsubstituted C₃₋₄ cycloalkyl or unsubstituted C₆₋₁₀cycloalkyl, and R¹ is a group selected from a substituted orunsubstituted: C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl, C₃₋₈cycloalkenyl, C₃₋₈ heterocycloalkenyl, aryl or heteroaryl moiety,wherein the aryl or heteroaryl moiety either contains 5 or 6 atoms in asingle ring or from 7 to 14 atoms in a fused polycyclic ring system; orD is unsubstituted cyclopentyl and R¹ is a substituted or unsubstituted:C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl, C₃₋₈ cycloalkenyl, C₃₋₈heterocycloalkenyl, aryl or heteroaryl moiety, wherein the aryl orheteroaryl moiety either contains 5 or 6 atoms in a single ring or from7 to 14 atoms in a fused polycyclic ring system, wherein the —C(═O)— andone of the substituents on the C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl,C₃₋₈ cycloalkenyl or C₃₋₈ heterocycloalkenyl moiety or the aryl orheteroaryl single ring are bonded to adjacent carbon atoms of R¹ and the—C(═O)— group is substituted on the aryl or heteroaryl fused polycyclicring system ortho to one of the two points of fusion of the polycyclicsystem.

In embodiments there are provided compounds of the invention, wherein:

X is C, Y is N; and

D is selected from substituted or unsubstituted: C₁₋₆ alkyl, C₃₋₁₀cycloalkenyl, C₆₋₁₀ aryl, 3 to 10 membered heterocycloalkyl, 3 to 10membered heterocycloalkenyl and 5 to 10 membered heteroaryl, substitutedC₃₋₁₀ cycloalkyl, unsubstituted C₃₋₄ cycloalkyl or unsubstituted C₆₋₁₀cycloalkyl, and R¹ is a group selected from a substituted orunsubstituted: C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl, C₃₋₈cycloalkenyl, C₃₋₈ heterocycloalkenyl, aryl or heteroaryl moiety,wherein the aryl or heteroaryl moiety either contains 5 or 6 atoms in asingle ring or from 7 to 14 atoms in a fused polycyclic ring system; orD is unsubstituted cyclopentyl and R¹ is a substituted or unsubstituted:C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl, C₃₋₈ cycloalkenyl, C₃₋₈heterocycloalkenyl, aryl or heteroaryl moiety, wherein the aryl orheteroaryl moiety either contains 5 or 6 atoms in a single ring or from7 to 14 atoms in a fused polycyclic ring system, wherein the —C(═O)— andone of the substituents on the C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl,C₃₋₈ cycloalkenyl or C₃₋₈ heterocycloalkenyl moiety or the aryl orheteroaryl single ring are bonded to adjacent carbon atoms of R¹ and the—C(═O)— group is substituted on the aryl or heteroaryl fused polycyclicring system ortho to one of the two points of fusion of the polycyclicsystem;orX is N, Y is C;D is selected from substituted or unsubstituted: C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, C₃₋₁₀ cycloalkenyl, C₆₋₁₀ aryl, 3 to 10 memberedheterocycloalkyl, 3 to 10 membered heterocycloalkenyl and 5 to 10membered heteroaryl; andR¹ is a group selected from a substituted or unsubstituted: C₃₋₈cycloalkyl, C₃₋₈ heterocycloalkyl, C₃₋₈ cycloalkenyl, C₃₋₈heterocycloalkenyl, aryl or heteroaryl moiety, wherein the aryl orheteroaryl moiety either contains 5 or 6 atoms in a single ring or from7 to 14 atoms in a fused polycyclic ring system.

In an embodiment of the invention there is provided a compound accordingto formula (X):

wherein B⁵ is CH or N and m is 1, 2, 3 or 4 (preferably m is 1 or 2);and at least one R⁷ is substituted orto to the —C(═O)— group.

In an embodiment there is provided a compound of formula (X) wherein R²is H. In a preferred embodiment, there is provided a compound of formula(X) wherein R³ and R⁴ are H, and R⁵ and R⁶ are H. In a particularlypreferred embodiment, there is provided a compound of formula (X)wherein R² is H, R³ and R⁴ are H, and R⁵ and R⁶ are H. In a preferredembodiment, there is provided a compound of formula (X), wherein A isunsubstituted or substituted phenyl or pyridyl (preferably unsubstitutedphenyl or fluorophenyl), R³ and R⁴ are H, and R⁵ and R⁶ are H. In anembodiment, there is provided a compound of formula (X), wherein A issubstituted or unsubstituted phenyl or pyridyl (preferably unsubstitutedphenyl or fluorophenyl), R³ and R⁴ are H, R⁵ and R⁶ are H, R² is H, andB⁵ is CH. R⁷ may be selected from: methoxy, fluoro, —OCF₃, OEt, O^(i)Pr,Cl, Me, CF₃, or CN (preferably R⁷ is methoxy). One R⁷ group may besubstituted at the two position. In other words the ring containing B⁵may be ortho substituted by one R⁷. Additional R⁷ groups may be present.Preferably, R⁷ is 2-methoxy.

In an embodiment the compounds of formula (X) A is phenyl orfluorophenyl.

In embodiments the compound of formula (I) may be a compound accordingto formulae (XI):

wherein zero, one or two B¹, B², B³ and B⁴ is N and the remaining areindependently selected from CH or CR⁷, andR⁷ is independently selected at each occurrence from: halo, —OR^(f),—NR^(f)R^(g), ═O, —CN, acyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkylsubstituted with —OR^(f), C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl,—SO₂R^(f), SO₃R^(f), —C(O)R^(f), —C(O)OR^(f), —C(O)NR^(f)R^(g) and aryloptionally substituted by 1 or 2 halo atoms.

Preferred compounds of the invention include:

Further preferred compounds of the invention include:

Compounds which may form part of the invention include:

Further compounds which may form part of the invention include:

Compounds of the invention may also be:

In another aspect of the invention there is provided a compound offormula (I) for use as a medicament.

In another aspect a compound of formula (I) is for use in the treatmentof a condition which is modulated by Bruton's tyrosine kinase (BTK).Usually conditions that are modulated by BTK are conditions that wouldbe treated by the inhibition of BTK using a compound of the presentinvention. A compound of formula (I) may be for use in the treatment ofa condition treatable by the inhibition of Bruton's tyrosine kinase(BTK).

BTK inhibition is a novel approach for treating many different humandiseases associated with the inappropriate activation of B-cells,including B-cell proliferative disorders, B-cell malignancies,immunological disease for example, autoimmune, heteroimmune conditions,and inflammatory disorders, or fibrosis. In particular, BTK inhibitionis a novel approach for treating many different human diseasesassociated with the inappropriate activation of B-cells, includingB-cell malignancies, immunological disease for example, autoimmune andinflammatory disorders.

In embodiments the condition treatable by the inhibition of BTK may beselected from: cancer, lymphoma, leukemia, autoimmune diseases,inflammatory disorders, heteroimune conditions, or fibrosis. Specificconditions treatable by the inhibition of BTK may be selected from:B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma,chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL,mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cellnon-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma,bone cancer, bone metastasis, follicular lymphoma, chronic lymphocyticlymphoma, B-cell prolymphocyte leukemia, lymphoplasmacytic lymphoma/,splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma,extranodal marginal zone B-cell lymphoma, nodal marginal zone B-celllymphoma, mediastinal (thymic) large B-cell lymphoma, intravascularlarge B-cell lymphoma, primary effusion lymphoma, burkittlymphoma/leukemia, lymphomatoid granulomatosis, inflammatory boweldisease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis,osteoarthritis, Still's disease, juvenile arthritis, diabetes,myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves'disease Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome,acute disseminated encephalomyelitis, Addison's disease,opsoclonus-myoclonus syndrome, ankylosing spondylitisis,antiphospholipid antibody syndrome, aplastic anemia, autoimmunehepatitis, coeliac disease, Goodpasture's syndrome, idiopathicthrombocytopenic purpura, optic neuritis, scleroderma, primary biliarycirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis,warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis,alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia,endometriosis, interstitial cystitis, neuromyotonia, scleroderma,vulvodynia, graft versus host disease, transplantation, transfusion,anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis,allergic rhinitis, atopic dermatitis, asthma, appendicitis, blepharitis,bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis,enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitissuppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis,pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usualinterstitial pneumonitis (UIP), interstitial lung disease, cryptogenicfibrosing alveolitis (CFA), bronchiolitis obliterans, bronchiectasis,fatty liver disease, steatosis (e.g., nonalcoholic steatohepatitis(NASH), cholestatic liver disease (e.g., primary biliary cirrhosis(PBC), cirrhosis, alcohol-induced liver fibrosis, biliary duct injury,biliary fibrosis, cholestasis or cholangiopathies. In some embodiments,hepatic or liver fibrosis includes, but is not limited to, hepaticfibrosis associated with alcoholism, viral infection, e.g., hepatitis(e.g., hepatitis C, B or D), autoimmune hepatitis, nonalcoholic fattyliver disease (NAFLD), progressive massive fibrosis, exposure to toxinsor irritants (e.g., alcohol, pharmaceutical drugs and environmentaltoxins), renal fibrosis (e.g., chronic kidney fibrosis), nephropathiesassociated with injury/fibrosis (e.g., chronic nephropathies associatedwith diabetes (e.g., diabetic nephropathy)), lupus, scleroderma of thekidney, glomerular nephritis, focal segmental glomerular sclerosis, IgAnephropathyrenal fibrosis associated with human chronic kidney disease(CKD), chronic progressive nephropathy (CPN), tubulointerstitialfibrosis, ureteral obstruction, chronic uremia, chronic interstitialnephritis, radiation nephropathy, glomerulosclerosis, progressiveglomerulonephrosis (PGN), endothelial/thrombotic microangiopathy injury,HIV-associated nephropathy, or fibrosis associated with exposure to atoxin, an irritant, or a chemotherapeutic agent, fibrosis associatedwith scleroderma; radiation induced gut fibrosis; fibrosis associatedwith a foregut inflammatory disorder such as Barrett's esophagus andchronic gastritis, and/or fibrosis associated with a hindgutinflammatory disorder, such as inflammatory bowel disease (IBD),ulcerative colitis and Crohn's disease, age-related maculardegeneration, diabetic retinopathy, retinopathy of prematurity andneovascular glaucoma

In embodiments the condition treatable by the inhibition of BTK may beselected from: cancer, lymphoma, leukemia, autoimmune diseases andinflammatory disorders. Specific conditions treatable by the inhibitionof BTK may be selected from: B-cell malignancy, B-cell lymphoma, diffuselarge B cell lymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphomafor example ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairycell leukemia B-cell non-Hodgkin lymphoma, Waldenstrom'smacroglobulinemia, multiple myeloma, bone cancer, bone metastasis,arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome,inflammatory bowel disease, Crohn's disease, lupus and Sjögren'ssyndrome.

B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma,chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL,mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cellnon-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma,bone cancer, bone metastasis, chronic lymphocytic lymphoma, B-cellprolymphocyte leukemia, lymphoplasmacytic lymphoma/, splenic marginalzone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginalzone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mediastinal(thymic) large B-cell lymphoma, intravascular large B-cell lymphoma,primary effusion lymphoma, burkitt lymphoma/leukemia, and lymphomatoidgranulomatosis are examples of cancer, lymphoma and leukemia treatableby BTK inhibition.

B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma,chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL,mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cellnon-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma,bone cancer and bone metastasis are examples of cancer, lymphoma andleukemia treatable by BTK inhibition.

Arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome,inflammatory bowel disease, Crohn's disease, lupus, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, Still's disease,juvenile arthritis, diabetes, myasthenia gravis, Hashimoto'sthyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome,Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison'sdisease, opsoclonus-myoclonus syndrome, ankylosing spondylitisis,antiphospholipid antibody syndrome, aplastic anemia, autoimmunehepatitis, coeliac disease, Goodpasture's syndrome, idiopathicthrombocytopenic purpura, optic neuritis, scleroderma, primary biliarycirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis,warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis,alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia,endometriosis, interstitial cystitis, neuromyotonia, scleroderma, andvulvodynia, asthma, appendicitis, blepharitis, bronchiolitis,bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis,conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis,mastitis, meningitis, myelitis myocarditis, myositis, nephritis,oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis,pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis,rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis,tonsillitis, uveitis, vaginitis, vasculitis, vulvitis graft versus hostdisease, transplantation, transfusion, anaphylaxis, allergy, type Ihypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopicdermatitis are examples of immunological diseases treatable by BTKinhibition.

Arthritis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis,bursitis, cervicitis, cholangitis, cholecystitis, colitis,conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis,mastitis, meningitis, myelitis myocarditis, myositis, nephritis,oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis,pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis,rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis,tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis are examplesof an inflammatory disorder treatable by BTK inhibition.

Lupus and Sjögren's syndrome, rheumatoid arthritis, psoriatic arthritis,osteoarthritis, Still's disease, juvenile arthritis, diabetes,myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves'disease, Sjogren's syndrome, Guillain-Barre syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylitisis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome,idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, psoriasis, alopecia universalis, Behcet's disease,chronic fatigue, dysautonomia, endometriosis, interstitial cystitis,neuromyotonia, scleroderma, and vulvodynia are examples of an autoimmunedisease treatable by BTK inhibition.

Graft versus host disease, transplantation, transfusion, anaphylaxis,allergy, type I hypersensitivity, allergic conjunctivitis, allergicrhinitis, and atopic dermatitis are examples of a heteroimmune conditiontreatable by BTK inhibition.

Pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usualinterstitial pneumonitis (UIP), interstitial lung disease, cryptogenicfibrosing alveolitis (CFA), bronchiolitis obliterans, bronchiectasis,fatty liver disease, steatosis (e.g., nonalcoholic steatohepatitis(NASH), cholestatic liver disease (e.g., primary biliary cirrhosis(PBC), cirrhosis, alcohol-induced liver fibrosis, biliary duct injury,biliary fibrosis, cholestasis or cholangiopathies. In some embodiments,hepatic or liver fibrosis includes, but is not limited to, hepaticfibrosis associated with alcoholism, viral infection, e.g., hepatitis(e.g., hepatitis C, B or D), autoimmune hepatitis, nonalcoholic fattyliver disease (NAFLD), progressive massive fibrosis, exposure to toxinsor irritants (e.g. alcohol, pharmaceutical drugs and environmentaltoxins), renal fibrosis (e.g. chronic kidney fibrosis), nephropathiesassociated with injury/fibrosis (e.g., chronic nephropathies associatedwith diabetes (e.g. diabetic nephropathy)), lupus, scleroderma of thekidney, glomerular nephritis, focal segmental glomerular sclerosis, IgAnephropathyrenal fibrosis associated with human chronic kidney disease(CKD), chronic progressive nephropathy (CPN), tubulointerstitialfibrosis, ureteral obstruction, chronic uremia, chronic interstitialnephritis, radiation nephropathy, glomerulosclerosis, progressiveglomerulonephrosis (PGN), endothelial/thrombotic microangiopathy injury,HIV-associated nephropathy, or fibrosis associated with exposure to atoxin, an irritant, a chemotherapeutic agent, fibrosis associated withscleroderma; radiation induced gut fibrosis; fibrosis associated with aforegut inflammatory disorder such as Barrett's esophagus and chronicgastritis, and/or fibrosis associated with a hindgut inflammatorydisorder, such as inflammatory bowel disease (IBD), ulcerative colitisand Crohn's disease, age-related macular degeneration, diabeticretinopathy, retinopathy of prematurity and neovascular glaucoma areexamples of fibrosis treatable by BTK inhibition.

Arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome,inflammatory bowel disease, Crohn's disease and lupus are examples ofimmunological diseases treatable by BTK inhibition. Arthritis is anexample of an inflammatory disorder treatable by BTK inhibition. Lupusand Sjögren's syndrome is an example of an autoimmune disease treatableby BTK inhibition.

Any of the conditions disclosed above as being treatable by BTKinhibition may be treated by a compound of the invention, or may betreated in a method comprising administering a compound of theinvention, or may be treated by a medicament manufactured through theuse of a compound of the present invention.

In embodiments, a compound of the invention may be for use in thetreatment of: cancer, lymphoma, leukemia, immunological diseases,autoimmune diseases and inflammatory disorders. The compound of theinvention may be for use in the treatment of specific conditionsselected from: B-cell malignancy, B-cell lymphoma, diffuse large B celllymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for exampleABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cellleukemia B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia,multiple myeloma, bone cancer, bone metastasis, arthritis, multiplesclerosis osteoporosis, irritable bowel syndrome, inflammatory boweldisease, Crohn's disease, Sjögren's syndrome and lupus. The compoundsmay also be used for the treatment of disorders associated with renaltransplant.

In an embodiment the compound of the invention may be for use in thetreatment of specific conditions selected from: B-cell malignancy,B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyteleukemia, non-Hodgkin lymphoma for example ABC-DLBCL, mantle celllymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkinlymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, lupus andarthritis.

In an aspect of the invention there is provided a method of treatment ofa condition which is modulated by Bruton's tyrosine kinase, wherein themethod comprises administering a therapeutic amount of a compound of theinvention, to a patient in need thereof.

The method of treatment may be a method of treating a conditiontreatable by the inhibition of Bruton's tyrosine kinase.

The invention also provides a method of treating a condition selectedfrom: cancer, lymphoma, leukemia, immunological diseases autoimmunediseases and inflammatory disorders, wherein the method comprisesadministering a therapeutic amount of a compound of the invention, to apatient in need thereof. The invention also provides a method oftreating a specific condition selected from: B-cell malignancy, B-celllymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia,non-Hodgkin lymphoma for example ABC-DLBCL, mantle cell lymphoma,follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin lymphoma,Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bonemetastasis, arthritis, multiple sclerosis osteoporosis, irritable bowelsyndrome, inflammatory bowel disease, Crohn's disease, Sjögren'ssyndrome and lupus, wherein the method comprises administering atherapeutic amount of a compound of formula (I), to a patient in needthereof. The method may also treat disorders associated with renaltransplant.

In an embodiment the method may be for treating a specific conditionselected from: B-cell malignancy, B-cell lymphoma, diffuse large B celllymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for exampleABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cellleukemia B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia,multiple myeloma, arthritis and lupus.

In another aspect of the invention there is provided a pharmaceuticalcomposition, wherein the composition comprises a compound of theinvention and pharmaceutically acceptable excipients.

In an embodiment the pharmaceutical composition may be a combinationproduct comprising an additional pharmaceutically active agent. Theadditional pharmaceutically active agent may be an anti-tumor agentdescribed below.

In certain embodiments the present invention does not include compoundsof formulae (X) and/or (XI).

D may be selected from substituted or unsubstituted: C₃₋₁₀ cycloalkyl,C₃₋₁₀ cycloalkenyl, C₆₋₁₀ aryl, 3 to 10 membered heterocycloalkyl, 3 to10 membered heterocycloalkenyl and 5 to 10 membered heteroaryl, wherein,when substituted, D contains from 1 to 9 substituents independentlyselected at each occurrence from: halo, —OR^(c), —NR^(c)R^(d), ═O,—C(O)OR^(c), —OC(O)R^(e), —C(O)NR^(c)R^(d), —NR^(c)C(O)R^(e), C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkyl substituted with —OR^(c), C₃₋₈cycloalkyl, —SO₂R^(c), SO₃R^(c), and a 5 to 8 membered heterocyclicgroup.

In an embodiment, D is selected from substituted or unsubstituted: C₁₋₆alkyl, C₅₋₉ cycloalkyl, C₅₋₉ cycloalkenyl, C₆₋₁₀ aryl, 5 to 9 memberedheterocycloalkyl, or 5, 6, 9 or 10 membered heteroaryl

In an embodiment D is not C₁₋₆ alkyl.

D may be substituted or unsubstituted, when substituted D contains 1 to5 substituents independently selected at each occurrence from the groupcomprising: halo, —OR^(c), —NR^(c)R^(d), ═O, —C(O)OR^(c), —OC(O)R^(e),—C(O)NR^(c)R^(d), —NR^(c)C(O)R^(e), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkyl substituted with —OR^(c), and a 5 to 8 membered heterocyclicgroup. The heterocyclic group may optionally be a heteroaryl group or ahetercycloalkyl group.

Optionally, D is not substituted pyrolidine, substituted piperidine,substituted azepane, amine substituted cyclopentyl, amine substitutedcyclohexyl, amine substituted cycloheptanyl or amine substituted phenyl.

The present invention provides compounds optionally with the provisothat when X is C and Y is N then D is not substituted with a groupselected from: C₁₋₄ alkyl, or:

wherein W is selected from H, methyl or CN and o is selected from 0, 1,2, 3 and 4.

The present invention provides compounds optionally with the provisothat when X is C and Y is N and D is substituted pyrolidine, substitutedpiperidine, substituted azepane, amine substituted cyclopentyl, aminesubstituted cyclohexyl, amine substituted cycloheptanyl or aminesubstituted phenyl then D is not substituted with a group selected from:C₁₋₄ alkyl, or:

wherein W is selected from H, methyl or CN and o is selected from 0, 1,2, 3 and 4.

The present invention provides compounds optionally with the provisothat when X is C and

Y is N then D is not substituted with a group selected from: C₁₋₄ alkyl,or:

wherein V is either O or NR^(y); W is selected from H, methyl or CN; ois selected from 0, 1, 2, 3 and 4; andR¹⁰⁰, R¹⁰¹, and R¹⁰² are independently selected from H, halo, —OR^(y),—CN, —NR^(y)R^(z), —CH₂NR^(y)R^(z), —CO₂R^(y), —C(O)R^(b),—C(O)NR^(y)R^(z), C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkyl substituted withC₃₋₈ cycloalkyl, C₁₋₆ alkyl substituted with C₃₋₈ heterocycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₃₋₈heterocycloalkyl, C₃₋₈ cycloalkenyl, C₃₋₈ heterocycloalkenyl, aryl,heteroaryl, alkaryl and alkheteroaryl;or R¹⁰⁰ and R¹⁰¹ taken together with the carbon atoms to which they areattached form a C₃₋₈ cycloalkene and R¹⁰² is independently selected asabove;or R¹⁰¹ and R¹⁰² taken together with the carbon atom to which they areattached form a C₃₋₈ cycloalkyl and R¹⁰⁰ is independently selected asabove;or R¹⁰⁰ and R¹⁰² taken together with the carbon atoms to which they areattached form a C—C triple bond and R¹⁰¹ is independently selected asabove,wherein R^(y) and R^(z) are independently selected at each occurrencefrom: H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ acyl, C₃₋₇ cycloalkyl, andC₃₋₇ halocycloalkyl.

The present invention provides compounds optionally with the provisothat D is not:

either a substituted or unsubstituted C₁₋₆ alkylene chain which issaturated or unsaturated and which may also contain, where chemicallypossible, 1, 2 or 3 N, O, or S atoms in the chain which areindependently chosen at each occurrence;

or wherein D does not represent a substituted or unsubstitutedcarbocyclic or heterocyclic moiety which is saturated or unsaturated andwhich contains from 3 to 8 atoms in the carbocyclic or heterocyclicring, wherein the ring is optionally substituted with —NR^(b)—, wherein—NR^(b)— is bonded to the ring; whenX is C and Y is N andD is substituted by a group selected from: C₁₋₄ alkyl, or:

wherein V is either O or NR^(y); W is selected from H, methyl or CN; ois selected from 0, 1, 2, 3 and 4; andR¹⁰⁰, R¹⁰¹, and R¹⁰² are independently selected from H, halo, —OR^(y),—CN, —NR^(y)R^(z), —CH₂NR^(y)R^(z), —CO₂R^(y), —C(O)R^(b),—C(O)NR^(y)R^(z), C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkyl substituted withC₃₋₈ cycloalkyl, C₁₋₆ alkyl substituted with C₃₋₈ heterocycloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₃₋₈heterocycloalkyl, C₃₋₈ cycloalkenyl, C₃₋₈ heterocycloalkenyl, aryl,heteroaryl, alkaryl and alkheteroaryl;or R¹⁰⁰ and R¹⁰¹ taken together with the carbon atoms to which they areattached form a C₃₋₈ cycloalkene and R¹⁰² is independently selected asabove;or R¹⁰¹ and R¹⁰² taken together with the carbon atom to which they areattached form a C₃₋₈ cycloalkyl and R¹⁰⁰ is independently selected asabove;or R¹⁰⁰ and R¹⁰² taken together with the carbon atoms to which they areattached form a C—C triple bond and R¹⁰¹ is independently selected asabove,wherein R^(y) and R^(z) are independently selected at each occurrencefrom: H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ acyl, C₃₋₇ cycloalkyl, andC₃₋₇ halocycloalkyl.

The provisos in the above four paragraphs occur when X is C and Y is N.In an embodiment the provisos may also independently occur when one of Xand Y is C and the other is N.

In certain embodiments when D is cyclopentyl then D is not substitutedwith 1 to 5 substituents independently selected at each occurrence fromthe group comprising: halo, —OR^(w), —SR^(w), —NR^(w)R^(x), NO, ═O, —CN,acyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, —SO₂R^(w), andSO₃R^(w), —C(O)R^(w) and C(O)OR^(w); wherein R^(w) and R^(x) areindependently selected at each occurrence from: H, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ acyl, C₃₋₇ cycloalkyl, and C₃₋₇ halocycloalkyl.

DETAILED DESCRIPTION

Given below are definitions of terms used in this application. Any termnot defined herein takes the normal meaning as the skilled person wouldunderstand the term.

The term “halo” refers to one of the halogens, group 17 of the periodictable. In particular the term refers to fluorine, chlorine, bromine andiodine. Preferably, the term refers to fluorine or chlorine.

The term “C₁₋₆ alkyl” refers to a linear or branched hydrocarbon chaincontaining 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl andn-hexyl. Alkylene groups may likewise be linear or branched and may havetwo places of attachment to the remainder of the molecule. Furthermore,an alkylene group may, for example, correspond to one of those alkylgroups listed in this paragraph. The alkyl and alkylene groups may beunsubstituted or substituted by one or more substituents. Possiblesubstituents are described below. Substituents for the alkyl group maybe halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C₁₋₆alkoxy.

The term “C₁₋₆ alkoxy” refers to an alkyl group which is attached to amolecule via oxygen. This includes moieties where the alkyl part may belinear or branched and may contain 1, 2, 3, 4, 5 or 6 carbon atoms, forexample methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,tert-butyl, n-pentyl and n-hexyl. Therefore, the alkoxy group may bemethoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy,tert-butoxy, n-pentoxy and n-hexoxy. The alkyl part of the alkoxy groupmay be unsubstituted or substituted by one or more substituents.Possible substituents are described below. Substituents for the alkylgroup may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH,C₁₋₆ alkoxy.

The term “C₁₋₆ haloalkyl” refers to a hydrocarbon chain substituted withat least one halogen atom independently chosen at each occurrence, forexample fluorine, chlorine, bromine and iodine. The halogen atom may bepresent at any position on the hydrocarbon chain. For example, C₁₋₆haloalkyl may refer to chloromethyl, flouromethyl, trifluoromethyl,chloroethyl e.g. 1-chloromethyl and 2-chloroethyl, trichloroethyl e.g.1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g.1-fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g.1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl,trichloropropyl, fluoropropyl, trifluoropropyl.

The term “C₂₋₆ alkenyl” refers to a branched or linear hydrocarbon chaincontaining at least one double bond and having 2, 3, 4, 5 or 6 carbonatoms. The double bond(s) may be present as the E or Z isomer. Thedouble bond may be at any possible position of the hydrocarbon chain.For example, the “C₂₋₆ alkenyl” may be ethenyl, propenyl, butenyl,butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

The term “C₂₋₆ alkynyl” refers to a branded or linear hydrocarbon chaincontaining at least one triple bond and having 2, 3, 4, 5 or 6 carbonatoms. The triple bond may be at any possible position of thehydrocarbon chain. For example, the “C₂₋₆ alkynyl” may be ethynyl,propynyl, butynyl, pentynyl and hexynyl.

The term “C₁₋₆ heteroalkyl” refers to a branded or linear hydrocarbonchain containing 1, 2, 3, 4, 5, or 6 carbon atoms and at least oneheteroatom selected from N, O and S positioned between any carbon in thechain or at an end of the chain. For example, the hydrocarbon chain maycontain one or two heteroatoms. The C₁₋₆ heteroalkyl may be bonded tothe rest of the molecule through a carbon or a heteroatom. For example,the “C₁₋₆ heteroalkyl” may be C₁₋₆ N-alkyl, C₁₋₆ N,N-alkyl, or C₁₋₆O-alkyl.

The term “carbocyclic” refers to a saturated or unsaturated carboncontaining ring system. A “carbocyclic” system may be monocyclic or afused polycyclic ring system, for example, bicyclic or tricyclic. A“carbocyclic” moiety may contain from 3 to 14 carbon atoms, for example,3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in apolycyclic system. “Carbocyclic” encompasses cycloalkyl moieties,cycloalkenyl moieties, aryl ring systems and fused ring systemsincluding an aromatic portion.

The term “heterocyclic” refers to a saturated or unsaturated ring systemcontaining at least one heteroatom selected from N, O or S. A“heterocyclic” system may contain 1, 2, 3 or 4 heteroatoms, for example1 or 2. A “heterocyclic” system may be monocyclic or a fused polycyclicring system, for example, bicyclic or tricyclic. A “heterocyclic” moietymay contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atomsin a monocyclic system and 7 to 14 carbon atoms in a polycyclic system.“Heterocyclic” encompasses heterocycloalkyl moieties, heterocycloalkenylmoieties and heteroaromatic moieties. For example, the heterocyclicgroup may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran,pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine,isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine,thiomorpholine, piperazine, and tetrahydropyran.

The term “cycloalkyl” refers to a saturated hydrocarbon ring system. The“cycloalkyl” group may be denoted as a “C₃₋₁₀ cycloalkyl” containing 3,4, 5, 6, 7, 8, 9 or 10 carbon atoms. The ring system may be a singlering or a bi-cyclic or tri-cyclic ring system. For example, the“cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,bicyclohexyl, cycloheptyl and cyclooctyl.

The term “cycloalkenyl” refers to an unsaturated hydrocarbon ring systemthat is not aromatic. The “cycloalkenyl” group may be denoted as a“C₃₋₁₀ cycloalkenyl”. A “C₃₋₁₀ cycloalkenyl” is a ring system containing3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The ring may contain more thanone double bond provided that the ring system is not aromatic. The ringsystem may be a single ring or a bi-cyclic or tri-cyclic ring system.For example, the “cycloalkenyl” may be cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly,cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

The term “heterocycloalkyl” refers to a saturated hydrocarbon ringsystem with at least one heteroatom within the ring selected from N, Oand S. The “heterocycloalkyl” group may be denoted as a “C₃₋₁₀heterocycloalkyl”. A “C₃₋₁₀ heterocycloalkyl” is a ring systemcontaining 3, 4, 5, 6, 7, 8, 9 or 10 atoms at least one being aheteroatom. For example there may be 1, 2 or 3 heteroatoms, optionally 1or 2. The “heterocycloalkyl” group may also be denoted as a “3 to 10membered heterocycloalkyl” which is also a ring system containing 3, 4,5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom. The ringsystem may be a single ring or a bi-cyclic or tri-cyclic ring system.Where the ring system is bicyclic one of the rings may be an aromaticring, for example as in indane. The “heterocycloalkyl” may be bonded tothe rest of the molecule through any carbon atom or heteroatom. The“heterocycloalkyl” may have one or more, e.g. one or two, bonds to therest of the molecule: these bonds may be through any of the atoms in thering. For example, the “heterocycloalkyl” may be oxirane, aziridine,azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine,succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine,isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine,tetrahydropyran, and indane.

The term “heterocycloalkenyl” refers to an unsaturated hydrocarbon ringsystem, that is not aromatic, having at least one heteroatom within thering selected from N, O and S. The “heterocycloalkenyl” group may bedenoted as a “C₃₋₁₀ heterocycloalkenyl”. A “C₃₋₁₀ heterocycloalkenyl” isa ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 atoms at least onebeing a heteroatom. For example there may be 1, 2 or 3 heteroatoms,optionally 1 or 2. The “heterocycloalkenyl” group may also be denoted asa “3 to 10 membered heterocycloalkenyl” which is also a ring systemcontaining 3, 4, 5, 6, 7, 8, 9 or 10 atoms at least one being aheteroatom. The ring system may be a single ring or a bi-cyclic ortri-cyclic ring system. Where the ring system is bicyclic one of therings may be an aromatic ring, for example as in indoline anddihydrobenzofuran.

The “heterocycloalkenyl” may be bonded to the rest of the moleculethrough any carbon atom or heteroatom. The “heterocycloalkenyl” may haveone or more, e.g. one or two, bonds to the rest of the molecule: thesebonds may be through any of the atoms in the ring. For example, the“C₃₋₈ heterocycloalkenyl” may be tetrahydropyridine, dihydropyran,dihydrofuran, pyrroline, dihydrobenzofuran, dihydrobenzothiophene andindoline.

The term “aromatic” when applied to a substituent as a whole means asingle ring or polycyclic ring system with 4n+2 electrons in aconjugated π system within the ring or ring system where all atomscontributing to the conjugated π system are in the same plane.

The term “aryl” refers to an aromatic hydrocarbon ring system. The ringsystem has 4n+2 electrons in a conjugated π system within a ring whereall atoms contributing to the conjugated π system are in the same plane.The ring system may be a single ring or a bi-cyclic or tri-cyclic ringsystem. For example, the “aryl” may be phenyl and naphthyl. The arylsystem itself may be substituted with other groups.

The term “heteroaryl” refers to an aromatic hydrocarbon ring system withat least one heteroatom within a single ring or within a fused ringsystem, selected from O, N and S. The ring or ring system has 4n+2electrons in a conjugated π system where all atoms contributing to theconjugated π system are in the same plane. The ring system may be asingle ring or a bi-cyclic or tri-cyclic ring system. For example, the“heteroaryl” may be imidazole, thiene, furane, thianthrene, pyrrol,benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.

The term “alkaryl” refers to an aryl group, as defined above, bonded toa C₁₋₄ alkyl, where the C₁₋₄ alkyl group provides attachment to theremainder of the molecule.

The term “alkheteroaryl” refers to a heteroaryl group, as defined above,bonded to a C₁₋₄ alkyl, where the alkyl group provides attachment to theremainder of the molecule.

The term “halogen” herein includes reference to F, Cl, Br and I. Halogenmay be Cl. Halogen may be F.

When —NR^(b)— is bonded to the carbocyclic or heterocyclic ring of D,the group E is bonded directly to —NR^(b)—.

A bond terminating in a “

” represents that the bond is connected to another atom that is notshown in the structure. A bond terminating inside a cyclic structure andnot terminating at an atom of the ring structure represents that thebond may be connected to any of the atoms in the ring structure whereallowed by valency.

Where a moiety is substituted, it may be substituted at any point on themoiety where chemically possible and consistent with atomic valencyrequirements. The moiety may be substituted by one or more substituents,e.g. 1, 2, 3 or 4 substituents; optionally there are 1 or 2 substituentson a group. Where there are two or more substituents, the substituentsmay be the same or different. The substituent(s) may be selected from:OH, NHR⁹, amidino, guanidino, hydroxyguanidino, formamidino,isothioureido, ureido, mercapto, C(O)H, acyl, acyloxy, carboxy, sulfo,sulfamoyl, carbamoyl, cyano, azo, nitro, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl or alkaryl. Where the group to be substituted is an alkylgroup the substituent may be ═O. Where the moiety is substituted withtwo or more substituents and two of the substituents are adjacent theadjacent substituents may form a C₄₋₈ ring along with the atoms of themoiety on which the substituents are substituted, wherein the C₄₋₈ ringis a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8carbon atoms or a saturated or unsaturated hydrocarbon ring with 4, 5,6, 7, or 8 carbon atoms and 1, 2 or 3 heteroatoms.

If chemically possible to do so, a cyclic substituent may be substitutedon a group so as to form a spiro-cycle.

Substituents are only present at positions where they are chemicallypossible, the person skilled in the art being able to decide (eitherexperimentally or theoretically) without inappropriate effort whichsubstitutions are chemically possible and which are not.

Ortho, meta and para substitution are well understood terms in the art.For the absence of doubt, “ortho” substitution is a substitution patternwhere adjacent carbons possess a substituent, whether a simple group,for example the fluoro group in the example below, or other portions ofthe molecule, as indicated by the bond ending in “

”.

“Meta” substitution is a substitution pattern where two substituents areon carbons one carbon removed from each other, i.e with a single carbonatom between the substituted carbons. In other words there is asubstituent on the second atom away from the atom with anothersubstituent. For example the groups below are meta substituted.

“Para” substitution is a substitution pattern where two substituents areon carbons two carbons removed from each other, i.e with two carbonatoms between the substituted carbons. In other words there is asubstituent on the third atom away from the atom with anothersubstituent. For example the groups below are para substituted.

By “acyl” is meant an organic radical derived from, for example, anorganic acid by the removal of the hydroxyl group, e.g. a radical havingthe formula R—C(O)—, where R may be selected from H, C₁₋₆ alkyl, C₃₋₈cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C₁₋₃ alkyl.In one embodiment acyl is alkyl-carbonyl. Examples of acyl groupsinclude, but are not limited to, formyl, acetyl, propionyl and butyryl.A particular acyl group is acetyl.

In embodiments where there is a single enantiomer of the compounds ofthe invention, the compounds of the invention may have an enantiomericpurity of at least about 90% enantiomeric excess (ee), at least about95% enantiomeric excess (ee), at least about 98% enantiomeric excess(ee), at least about 99% enantiomeric excess (ee), or 100% enantiomericexcess (ee). In embodiments where there is a mixture of enantiomers ofthe compounds of the invention, the compounds of the invention may be aracemic mixture or any other mixture of enantiomers, for example thecompounds of the invention may have an enantiomeric purity of at leastabout 50% enantiomeric excess (ee), at least about 60% enantiomericexcess (ee), at least about 70% enantiomeric excess (ee), at least about80% enantiomeric excess (ee), at least about 90% enantiomeric excess(ee), or at least about 95% enantiomeric excess (ee).

Throughout the description the disclosure of a compound also encompassespharmaceutically acceptable salts, solvates and stereoisomers thereof.Where a compound has a stereocentre, both (R) and (S) stereoisomers arecontemplated by the invention, equally mixtures of stereoisomers or aracemic mixture are completed by the present application. Where acompound of the invention has two or more stereocentres any combinationof (R) and (S) stereoisomers is contemplated. The combination of (R) and(S) stereoisomers may result in a diastereomeric mixture or a singlediastereoisomer. The compounds of the invention may be present as asingle stereoisomer or may be mixtures of stereoisomers, for exampleracemic mixtures and other enantiomeric mixtures, and diasteroemericmixtures. Where the mixture is a mixture of enantiomers the enantiomericexcess may be any of those disclosed above. Where the compound is asingle stereoisomer the compounds may still contain otherdiasteroisomers or enantiomers as impurities. Hence a singlestereoisomer does not necessarily have an enantiomeric excess (e.e.) ordiastereomeric excess (d.e.) of 100% but could have an e.e. or d.e. ofabout at least 85%

The invention contemplates pharmaceutically acceptable salts of thecompounds of formula (I). These may include the acid addition and basesalts of the compounds. These may be acid addition and base salts of thecompounds. In addition the invention contemplates solvates of thecompounds. These may be hydrates or other solvated forms of thecompound.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include the acetate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulfate, naphthylate,1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate andtrifluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts. Hemisalts of acids andbases may also be formed, for example, hemisulfate and hemicalciumsalts. For a review on suitable salts, see “Handbook of PharmaceuticalSalts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of compounds of formula (I) may beprepared by one or more of three methods:

(i) by reacting the compound of formula (I) with the desired acid orbase;

(ii) by removing an acid- or base-labile protecting group from asuitable precursor of the compound of formula (I) or by ring-opening asuitable cyclic precursor, for example, a lactone or lactam, using thedesired acid or base; or

(iii) by converting one salt of the compound of formula (I) to anotherby reaction with an appropriate acid or base or by means of a suitableion exchange column.

All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionisation in theresulting salt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and a stoichiometric amount ofone or more pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ is employed when said solvent is water.

Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionised, partially ionised, or non-ionised. For a review of suchcomplexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August1975).

Hereinafter all references to compounds of any formula includereferences to salts, solvates and complexes thereof and to solvates andcomplexes of salts thereof.

The compounds of the invention include compounds of a number of formulaas herein defined, including all polymorphs and crystal habits thereof,prodrugs and isomers thereof (including optical, geometric andtautomeric isomers) as hereinafter defined and isotopically-labeledcompounds of the invention.

Before purification, the compounds of the present invention may exist asa mixture of enantiomers depending on the synthetic procedure used. Theenantiomers can be separated by conventional techniques known in theart. Thus the invention covers individual enantiomers as well asmixtures thereof.

For some of the steps of the process of preparation of the compounds offormula (I), it may be necessary to protect potential reactive functionsthat are not wished to react, and to cleave said protecting groups inconsequence. In such a case, any compatible protecting radical can beused. In particular methods of protection and deprotection such as thosedescribed by T.W. GREENE (Protective Groups in Organic Synthesis, A.Wiley-Interscience Publication, 1981) or by P. J. Kocienski (Protectinggroups, Georg Thieme Verlag, 1994), can be used. All of the abovereactions and the preparations of novel starting materials used in thepreceding methods are conventional and appropriate reagents and reactionconditions for their performance or preparation as well as proceduresfor isolating the desired products will be well-known to those skilledin the art with reference to literature precedents and the examples andpreparations hereto.

Also, the compounds of the present invention as well as intermediatesfor the preparation thereof can be purified according to variouswell-known methods, such as for example crystallization orchromatography.

The method of treatment or the compound for use in the treatment ofcancer, lymphoma, leukemia or immunological diseases as definedhereinbefore may be applied as a sole therapy or be a combinationtherapy with an additional active agent.

The method of treatment or the compound for use in the treatment ofcancer, lymphoma or leukemia may involve, in addition to the compound ofthe invention, conventional surgery or radiotherapy or chemotherapy.Such chemotherapy may include one or more of the following categories ofanti-tumor agents:

(i) antiproliferative/antineoplastic drugs and combinations thereof,such as alkylating agents (for example cis-platin, oxaliplatin,carboplatin, cyclophosphamide, nitrogen mustard, bendamustin, melphalan,chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites(for example gemcitabine and antifolates such as fluoropyrimidines like5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed,cytosine arabinoside, and hydroxyurea); antibiotics (for exampleanthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);antimitotic agents (for example vinca alkaloids like vincristine,vinblastine, vindesine and vinorelbine and taxoids like taxol andtaxotere and polokinase inhibitors); proteasome inhibitors, for examplecarfilzomib and bortezomib; interferon therapy; and topoisomeraseinhibitors (for example epipodophyllotoxins like etoposide andteniposide, amsacrine, topotecan, mitoxantrone and camptothecin);(ii) cytostatic agents such as antiestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of 5α-reductase suchas finasteride;(iii) anti-invasion agents, for example dasatinib and bosutinib(SKI-606), and metalloproteinase inhibitors, inhibitors of urokinaseplasminogen activator receptor function or antibodies to Heparanase;(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies,for example the anti-erbB2 antibody trastuzumab [Herceptin™], theanti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab,tyrosine kinase inhibitors, for example inhibitors of the epidermalgrowth factor family (for example EGFR family tyrosine kinase inhibitorssuch as gefitinib, erlotinib and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib);inhibitors of the hepatocyte growth factor family; inhibitors of theinsulin growth factor family; modulators of protein regulators of cellapoptosis (for example Bcl-2 inhibitors); inhibitors of theplatelet-derived growth factor family such as imatinib and/or nilotinib(AMN107); inhibitors of serine/threonine kinases (for example Ras/Rafsignalling inhibitors such as farnesyl transferase inhibitors, forexample sorafenib, tipifarnib and lonafarnib), inhibitors of cellsignalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinaseinhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinaseinhibitors, IGF receptor, kinase inhibitors; aurora kinase inhibitorsand cyclin dependent kinase inhibitors such as CDK2 and/or CDK4inhibitors;(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™);thalidomide; lenalidomide; and for example, a VEGF receptor tyrosinekinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib andpazopanib;(vi) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2;(vii) immunotherapy approaches, including for example antibody therapysuch as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) andofatumumab; interferons such as interferon α; interleukins such as IL-2(aldesleukin); interleukin inhibitors for example IRAK4 inhibitors;cancer vaccines including prophylactic and treatment vaccines such asHPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel-T(Provenge); and toll-like receptor modulators for example TLR-7 or TLR-9agonists; and(viii) cytotoxic agents for example fludaribine (fludara), cladribine,pentostatin (Nipent™);(ix) steroids such as corticosteroids, including glucocorticoids andmineralocorticoids, for example aclometasone, aclometasone dipropionate,aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate,betamethasone, betamethasone dipropionate, betamethasone sodiumphosphate, betamethasone valerate, budesonide, clobetasone, clobetasonebutyrate, clobetasol propionate, cloprednol, cortisone, cortisoneacetate, cortivazol, deoxycortone, desonide, desoximetasone,dexamethasone, dexamethasone sodium phosphate, dexamethasoneisonicotinate, difluorocortolone, fluclorolone, flumethasone,flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide,fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolonecaproate, fluocortolone pivalate, fluorometholone, fluprednidene,fluprednidene acetate, flurandrenolone, fluticasone, fluticasonepropionate, halcinonide, hydrocortisone, hydrocortisone acetate,hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisonebuteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate,meprednisone, methylprednisolone, mometasone paramethasone, mometasonefuroate monohydrate, prednicarbate, prednisolone, prednisone,tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide,triamcinolone alcohol and their respective pharmaceutically acceptablederivatives. A combination of steroids may be used, for example acombination of two or more steroids mentioned in this paragraph;(x) targeted therapies, for example PI3Kd inhibitors, for exampleidelalisib and perifosine.

The method of treatment or the compound for use in the treatment ofimmunological diseases may involve, in addition to the compound of theinvention, additional active agents. The additional active agents may beone or more active agents used to treat the condition being treated bythe compound of formula (I) and additional active agent. The additionalactive agents may include one or more of the following active agents: —

(i) steroids such as corticosteroids, including glucocorticoids andmineralocorticoids, for example aclometasone, aclometasone dipropionate,aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate,betamethasone, betamethasone dipropionate, betamethasone sodiumphosphate, betamethasone valerate, budesonide, clobetasone, clobetasonebutyrate, clobetasol propionate, cloprednol, cortisone, cortisoneacetate, cortivazol, deoxycortone, desonide, desoximetasone,dexamethasone, dexamethasone sodium phosphate, dexamethasoneisonicotinate, difluorocortolone, fluclorolone, flumethasone,flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide,fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolonecaproate, fluocortolone pivalate, fluorometholone, fluprednidene,fluprednidene acetate, flurandrenolone, fluticasone, fluticasonepropionate, halcinonide, hydrocortisone, hydrocortisone acetate,hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisonebuteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate,meprednisone, methylprednisolone, mometasone paramethasone, mometasonefuroate monohydrate, prednicarbate, prednisolone, prednisone,tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide,triamcinolone alcohol and their respective pharmaceutically acceptablederivatives. A combination of steroids may be used, for example acombination of two or more steroids mentioned in this paragraph;(ii) TNF inhibitors for example etanercept; monoclonal antibodies (e.g.infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia),golimumab (Simponi)); fusion proteins (e.g. etanercept (Enbrel)); and5-HT_(2A) agonists (e.g. 2,5-dimethoxy-4-iodoamphetamine, TCB-2,lysergic acid diethylamide (LSD), lysergic acid dimethylazetidide);(iii) anti-inflammatory drugs, for example non-steroidalanti-inflammatory drugs;(iv) dihydrofolate reductase inhibitors/antifolates, for examplemethotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim,pemetrexed, ralitrexed and pralatrexate; and(v) immunosuppressants for example cyclosporins, tacrolimus, sirolimuspimecrolimus, angiotensin II inhibitors (e.g. Valsartan, Telmisartan,Losartan, Irbesatan, Azilsartan, Olmesartan, Candesartan, Eprosartan)and ACE inhibitors e.g. sulfhydryl-containing agents (e.g. Captopril,Zofenopril), dicarboxylate-containing agents (e.g. Enalapril, Ramipril,Quinapril, Perindopril, Lisinopril, Benazepril, Imidapril, Zofenopril,Trandolapril), phosphate-containing agents (e.g. Fosinopril),casokinins, lactokinins and lactotripeptides.

Such combination treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within a therapeutically effective dosage range describedhereinbefore and the other pharmaceutically-active agent within itsapproved dosage range.

According to a further aspect of the invention there is provided apharmaceutical product comprising a compound of formula (I), or apharmaceutically acceptable salt thereof as defined hereinbefore and anadditional active agent. The additional active agent may be ananti-tumour agent as defined hereinbefore for the combination treatmentof a condition modulated by BTK.

According to a further aspect of the invention there is provided amethod of treatment a condition modulated by BTK comprisingadministering a therapeutically effective amount of a compound offormula (I), or a pharmaceutically acceptable salt thereofsimultaneously, sequentially or separately with an additional anti-tumoragent, as defined hereinbefore, to a patient in need thereof.

According to a further aspect of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereoffor use simultaneously, sequentially or separately with an additionalanti-tumour agent as defined hereinbefore, in the treatment of acondition modulated by BTK.

According to another aspect of the invention there is provided a use ofthe compound of formula (I) in combination with an anti-tumor agent ashereinbefore described. The compound of formula (I) may be usedsimultaneously, sequentially or separately with the additionalanti-tumor agent The use may be in a single combination productcomprising the compound of formula (I) and the anti-tumor agent.

According to a further aspect there is provided a method of providing acombination product, wherein the method comprises providing a compoundof formula (I) simultaneously, sequentially or separately with ananti-tumor agent, as defined hereinbefore. The method may comprisecombining the compound of formula (I) and the anti-tumor agent in asingle dosage form. Alternatively the method may comprise providing theanti-tumor agent as separate dosage forms.

According to a further aspect there is provided a method of providing acombination product, wherein the method comprises providing a compoundof formula (I) simultaneously, sequentially or separately with ananti-tumor agent, as defined hereinbefore. The method may comprisecombining the compound of formula (I) and the anti-tumor agent in asingle dosage form. Alternatively the method may comprise providing theanti-tumor agent as separate dosage forms.

The condition modulated by BTK described above may be cancer, leukemiaor cancer. More specifically the condition modulated by BTK may beselected from: B-cell malignancy, B-cell lymphoma, diffuse large B celllymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for exampleABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cellleukemia B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemiaand multiple myeloma.

Compounds of the invention may exist in a single crystal form or in amixture of crystal forms or they may be amorphous. Thus, compounds ofthe invention intended for pharmaceutical use may be administered ascrystalline or amorphous products. They may be obtained, for example, assolid plugs, powders, or films by methods such as precipitation,crystallization, freeze drying, or spray drying, or evaporative drying.Microwave or radio frequency drying may be used for this purpose.

For the above-mentioned compounds of the invention the dosageadministered will, of course, vary with the compound employed, the modeof administration, the treatment desired and the disorder indicated. Forexample, if the compound of the invention is administered orally, thenthe daily dosage of the compound of the invention may be in the rangefrom 0.01 micrograms per kilogram body weight (μg/kg) to 100 milligramsper kilogram body weight (mg/kg).

A compound of the invention, or pharmaceutically acceptable saltthereof, may be used on their own but will generally be administered inthe form of a pharmaceutical composition in which the compounds of theinvention, or pharmaceutically acceptable salt thereof, is inassociation with a pharmaceutically acceptable adjuvant, diluent orcarrier. Conventional procedures for the selection and preparation ofsuitable pharmaceutical formulations are described in, for example,“Pharmaceuticals—The Science of Dosage Form Designs”, M. E. Aulton,Churchill Livingstone, 1988.

Depending on the mode of administration of the compounds of theinvention, the pharmaceutical composition which is used to administerthe compounds of the invention will preferably comprise from 0.05 to 99%w (percent by weight) compounds of the invention, more preferably from0.05 to 80% w compounds of the invention, still more preferably from0.10 to 70% w compounds of the invention, and even more preferably from0.10 to 50% w compounds of the invention, all percentages by weightbeing based on total composition.

The pharmaceutical compositions may be administered topically (e.g. tothe skin) in the form, e.g., of creams, gels, lotions, solutions,suspensions, or systemically, e.g. by oral administration in the form oftablets, capsules, syrups, powders or granules; or by parenteraladministration in the form of a sterile solution, suspension or emulsionfor injection (including intravenous, subcutaneous, intramuscular,intravascular or infusion); by rectal administration in the form ofsuppositories; or by inhalation in the form of an aerosol.

For oral administration the compounds of the invention may be admixedwith an adjuvant or a carrier, for example, lactose, saccharose,sorbitol, mannitol; a starch, for example, potato starch, corn starch oramylopectin; a cellulose derivative; a binder, for example, gelatine orpolyvinylpyrrolidone; and/or a lubricant, for example, magnesiumstearate, calcium stearate, polyethylene glycol, a wax, paraffin, andthe like, and then compressed into tablets. If coated tablets arerequired, the cores, prepared as described above, may be coated with aconcentrated sugar solution which may contain, for example, gum arabic,gelatine, talcum and titanium dioxide. Alternatively, the tablet may becoated with a suitable polymer dissolved in a readily volatile organicsolvent.

For the preparation of soft gelatine capsules, the compounds of theinvention may be admixed with, for example, a vegetable oil orpolyethylene glycol. Hard gelatine capsules may contain granules of thecompound using either the above-mentioned excipients for tablets. Alsoliquid or semisolid formulations of the compound of the invention may befilled into hard gelatine capsules. Liquid preparations for oralapplication may be in the form of syrups or suspensions, for example,solutions containing the compound of the invention, the balance beingsugar and a mixture of ethanol, water, glycerol and propylene glycol.Optionally such liquid preparations may contain colouring agents,flavouring agents, sweetening agents (such as saccharine), preservativeagents and/or carboxymethylcellulose as a thickening agent or otherexcipients known to those skilled in art.

For intravenous (parenteral) administration the compounds of theinvention may be administered as a sterile aqueous or oily solution.

The size of the dose for therapeutic purposes of compounds of theinvention will naturally vary according to the nature and severity ofthe conditions, the age and sex of the animal or patient and the routeof administration, according to well-known principles of medicine.

Dosage levels, dose frequency, and treatment durations of compounds ofthe invention are expected to differ depending on the formulation andclinical indication, age, and co-morbid medical conditions of thepatient. The standard duration of treatment with compounds of theinvention is expected to vary between one and seven days for mostclinical indications. It may be necessary to extend the duration oftreatment beyond seven days in instances of recurrent infections orinfections associated with tissues or implanted materials to which thereis poor blood supply including bones/joints, respiratory tract,endocardium, and dental tissues.

EXAMPLES AND SYNTHESIS

As used herein the following terms have the meanings given: “Boc” refersto tert-butoxycarbonyl; “DCM” refers to dichloromethane; “DIPEA” refersto N,N-Diisopropylethylamine; “LCMS” refers to liquidchromatography/mass spectrometry; “MIM” refers to monoisotopic mass;“min” refers to minutes; “NMP” refers to N-methylpyrrolidinone; “TLC”refers to thin layer chromatography; “Rf” refers to Retention factor;“RT” refers to retention time; “SCX” refers to strong cation exchange;“TFA” refers to trifluoroacetic acid; “THF” refers to tetrahydrofuran;and “TBME” refers to tert-Butyl methyl ether.

Solvents, reagents and starting materials were purchased from commercialvendors and used as received unless otherwise described. All reactionswere performed at room temperature unless otherwise stated.

Compound identity and purity confirmations were performed by LCMS UVusing a Waters Acquity SQ Detector 2 (ACQ-SQD2# LCA081). The diode arraydetector wavelength was 254 nM and the MS was in positive and negativeelectrospray mode (m/z: 150-800). A 2 μL aliquot was injected onto aguard column (0.2 μm×2 mm filters) and UPLC column (C18, 50×2.1 mm, <2μm) in sequence maintained at 40° C. The samples were eluted at a flowrate of 0.6 mL/min with a mobile phase system composed of A (0.1% (v/v)Formic Acid in Water) and B (0.1% (v/v) Formic Acid in Acetonitrile)according to the gradients outlined in Table 1 below. Retention times RTare reported in minutes.

TABLE 1 Time (min) % A % B Long Acidic 0 95 5 1.1 95 5 6.1 5 95 7 5 957.5 95 5 8 95 5 Short acidic 0 95 5 0.3 95 5 2 5 95 2.6 95 5 3 95 5

Compound identity confirmations were also performed by LCMS UV using aWaters Alliance 2695 micromass ZQ (K98SM4 512M-LAA434). The diode arraydetector wavelength was 254 nM and the MS was in positive and negativeelectrospray mode (m/z: 150-650). A 10 μL aliquot was injected onto anHPLC column (C18, 75×4.6 mm, 2.5 μm) at room temperature which wascontrolled at 19° C. The samples were eluted at a flow rate of 0.9mL/min with a mobile phase system composed of A (0.1% (v/v) Formic Acidin 95:5 (v/v) Water: Acetonitrile) and B (0.1% (v/v) Formic Acid in 95:5(v/v) Acetonitrile: Water) according to the gradients outlined in Table2 below. Retention times RT are reported in minutes.

TABLE 2 Method 1 Time (min) % A % B 0 100 0 5.5 0 100 6.0 5 100 6.5 1000 7 100 0

Compound identity and purity confirmations were performed by LCMS UVusing a Waters Alliance 2790 Micromass ZQ (C00SM0 019M LAB1923). Thediode array detector wavelength was 254 nM and the MS was in positiveand negative electrospray mode (m/z: 100-850). A 10 μL aliquot wasinjected onto an HPLC column (C18, 50×2.0 mm, 5 μm) at room temperature(20° C.). The samples were eluted at a flow rate of 0.8 mL/min with amobile phase system composed of A (HPLC-grade Water); B (0.1%(HPLC-grade Acetonitrile); C (1.0% (v/v) Formic Acid in 50:50 (v/v)Water:Acetonitrile) and D (1.0% (v/v) Ammonia in 50:50 (v/v)Water:Acetonitrile) according to the gradients outlined in Table 3below. Retention times RT are reported in minutes.

TABLE 3 Time (min) % A % B % C % D Method 2 (5 minute acidic) 0 90 5 5 04.0 0 95 5 0 4.49 0 95 5 0 4.5 95 5 0 0 Method 3 (7 minute acidic) 0 905 5 0 0.5 90 5 5 0 5.0 0 95 5 0 5.49 0 95 5 0 6.0 90 10 0 0 7.0 90 10 00 Method 4 (15 minute acidic) 0 95 0 5 0 2.0 95 0 5 0 12.0 0 95 5 0 14.00 95 5 0 14.1 95 0 5 0

NMR was also used to characterise final compounds. NMR spectra wereobtained on a Bruker AVIII 400 Nanobay with 5 mm BBFO probe. Optionally,compound Rf values on silica thin layer chromatography (TLC) plates weremeasured.

Compound purification was performed by flash column chromatography onsilica or by preparative LCMS. LCMS purification was performed using aWaters 3100 Mass detector in positive and negative electrospray mode(m/z: 150-800) with a Waters 2489 UV/Vis detector. Samples were elutedat a flow rate of 20 mL/min on a XBridge™ prep C18 5 μM OBD 19×100 mmcolumn with a mobile phase system composed of A (0.1% (v/v) Formic Acidin Water) and B (0.1% (v/v) Formic Acid in Acetonitrile) according tothe gradient outlined in Table 4 below.

TABLE 4 Time (min) % A % B 0 90 10 1.5 90 10 11.7 5 95 13.7 5 95 14 9090 15 90 90

Chemical names in this document were generated using mol2nam-Structureto Name Conversion by OpenEye Scientific Software. Starting materialswere purchased from commercial sources or synthesised according toliterature procedures.

General Procedures

General Procedure A

To a suspension of 4-(aminomethyl)phenyl]boronic acid hydrochloride (1.1eq.) and the corresponding benzoic acid (1.0 eq.) in anhydrous THF (0.49M), under a nitrogen atmosphere, was added successively,N,N-diisopropylethylamine (5.0 eq.) and propylphosphonic anhydride (50%wt in EtOAc) (1.5 eq.). The reaction mixture was heated under reflux at70° C. overnight with stirring. The mixture was diluted with water andDCM, then partitioned. The aqueous layer was extracted with DCM (×2).The combined organic extracts were filtered over a phase separator andconcentrated under reduced pressure to afford the desired boronic acid.No further purification was attempted and the product was used directlyin the next step.

General Procedure B

To a suspension of 4-(aminomethyl)phenyl]boronic acid hydrochloride (1.0eq.) and DIPEA (3.0 eq.) in anhydrous THF (0.2 M) under a nitrogenatmosphere was added a solution of the corresponding benzoyl chloridederivative (1.1 eq.) in anhydrous THF (0.2 M). The reaction mixture wasstirred overnight at room temperature, quenched with a saturated aqueoussolution of ammonium chloride and then extracted into ethyl acetate(×3). The combined organics were washed with brine, dried over Na₂SO₄and filtered then concentrated under reduced pressure to afford thedesired boronic acid derivative. No further purification was attemptedand the product was used directly in the next step.

General Procedure C

A mixture of halide (1.0 eq.), boronic acid or pinacol ester (1.5 eq.)and potassium carbonate (2.0 eq.) in 1,4-dioxane and water (3:1, 0.1 M)was degassed by bubbling nitrogen through it for 25 min.1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (0.05 eq.) was added and the mixture wasdegassed again by bubbling nitrogen through it for 30 min. The mixturewas then heated at 120° C. for 14 h. The reaction mixture was filteredover Celite®. The cake was rinsed with DCM. Water was added to thefiltrate and the layers were partitioned. The aqueous layer wasextracted with DCM (×2). The combined organic extracts were filteredover phase separator and then concentrated under reduced pressure togive a dark solid. Further purification by flash column chromatography(DCM/MeOH 100:0 to 90:10) gave the desired compound.

General Procedure D

A mixture of halide (1.0 eq.), boronic acid or pinacol ester (1.5 eq.)and potassium carbonate (2.0 eq.) in 1,4-dioxane and water (3:1, 0.1 M)was degassed by bubbling nitrogen through it for 15 min.1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (0.05 eq.) was added and the mixture wasdegassed again by bubbling nitrogen through it for 15 min. The mixturewas then heated under microwave irradiation at 120-140° C. for 60-90min. The reaction mixture was either purified by SCX SPE cartridge andused as such or purified using the following procedure, unless statedused crude. The mixture filtered over Celite®. The cake was rinsed withDCM. Water was added to the filtrate and the layers were partitioned.The aqueous layer was extracted with DCM (×2). The combined organicextracts were filtered over phase separator and then concentrated underreduced pressure to give a dark solid. Further purification by flashcolumn chromatography gave the desired compound.

General Procedure E

A mixture of tert-butyl derivative (1.0 eq), formic acid (285.0 eq) andconcentrated hydrochloric acid (44 eq) was heated to reflux and stirredfor 90 min. Upon completion, the reaction mixture was cooled to roomtemperature and concentrated to dryness. The resulting residue waspurified by SCX SPE cartridge to give the desired compound.

General Procedure F

To a suspension of amine (1.0 eq.) and acid (1.0 eq.) in anhydrous THF(0.3 M) were added successively N,N-diisopropylethylamine (3.0 eq.) andpropylphosphonic anhydride (1.5 eq.). The reaction mixture was stirredovernight at room temperature, diluted with water and DCM. The layerswere partitioned. The aqueous layer was extracted with DCM (×2). Thecombined organic extracts were filtered over phase separator andconcentrated to give a foam. Further purification by flash columnchromatography on silica gel gave the title compound.

General Procedure G

To a suspension of nucleophile (1.0 eq), corresponding alcohol (1.7 eq)and triphenylphosphine (1.7 eq) in anhydrous THF (0.18 M), cooled to−10° C., was added diisopropyl azodicarboxylate (1.7 eq) dropwise whilekeeping the internal temperature below −8° C. The reaction mixture wasallowed to return to room temperature over 30 min, stirred overnight andthen concentrated under reduced pressure. Further purification by flashcolumn chromatography (EtOAc/MeOH 100:0 to 80:20) afforded the desiredproduct.

General Procedure H

To a solution of acetyl derivative (1.0 eq) in anhydrous MeOH (0.05 M),at room temperature under a N₂ atmosphere, was added a 30% sodiummethoxide solution in MeOH (2.0 eq). The reaction mixture was stirredfor 30 min, partitioned between EtOAc and water. The aqueous layer wasextracted with EtOAc. The combined organic extracts were dried overNa₂SO₄ and concentrated under vacuum to give the desired product.

General Procedure I

A solution of pivalate derivative (1.0 eq) in DCM (0.03 M) undernitrogen was treated with 1 M diisobutylaluminium hydride in heptane(2.0 eq) at −78° C. The reaction was stirred for 1 h before beingquenched with MeOH (5 mL) and evaporated in vacuo. The crude materialwas purified by flash column chromatography (EtOAc/MeOH 100:0 to 60:40)to give the desired product.

General Procedure J

To a solution of potassium hydroxide (6.0 eq) in a DMSO/water mixture (1M, 4:1) was added a solution of pivalate derivative (1.0 eq) in aDMSO/water mixture (0.03 M, 4:1). The reaction mixture was heated to 80°C. and stirred for 15 min, cooled to room temperature and thenpartitioned between DCM and water. The aqueous layer was extracted withDCM. The combined organic extracts were dried over Na₂SO₄ andconcentrated under vacuum. The crude material was purified by flashcolumn chromatography on silica gel to give the desired product.

General Procedure K

A mixture of halide derivative (1.0 eq.), Molander salt (1.0 eq.),cesium carbonate (3.0 eq.) and XPhos (0.1 eq) in THF and water (10:1,0.14 M) was degassed by bubbling nitrogen through it for 15 min.Palladium acetate (0.05 eq.) was then added and the mixture was degassedagain by bubbling nitrogen through it for 5 min. The mixture was thenheated to 85° C. for 16 h, filtered over Celite®. The cake was rinsedwith DCM. Water was added to the filtrate and the layers werepartitioned. The aqueous layer was extracted with DCM (×2). The combinedorganic extracts were filtered over phase separator and thenconcentrated under reduced pressure. Further purification by flashcolumn chromatography on silica gel gave the desired compound.

General Procedure L

To a stirred solution of alcohol (1.0 eq) in DCM (0.9 M), cooled at 0°C. under a nitrogen atmosphere, was added triethylamine (1.1 eq). Theresulting solution was left to stir for 10 minutes before addingdropwise methanesulfonyl chloride (1.1 eq). The reaction mixture wasstirred at 0° C. for 1 h, quenched with water, and extracted with DCM(×2). The combined organic extracts were filtered over a phase separatorand concentrated under reduced pressure to afford the desired mesylatedproduct.

General Procedure M

A mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.0 eq),mesylated alcohol (1.2 eq), and cesium carbonate (2.5 eq) in DMF (0.2 M)was heated to 80° C. and stirred for 16 h. Once cooled, the reactionmixture was concentrated under reduced pressure to leave a brownresidue. EtOAc was added and the mixture was then sonicated thenfiltered. The filtrate was washed with water (×2) then brine (×2), driedover Na₂SO₄ and concentrated under vacuum. Further purification by flashcolumn chromatography on silica gel afforded the desired compound.

General Procedure N

To a nitrogen degassed solution of potassium acetate (3.0 eq),bis(pinacolato)diboron (1.5 eq) and halide derivative (1.0 eq) in1,4-dioxane (0.12 M) was added1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (0.05 eq). The reaction mixture was thendegassed with nitrogen for a further 5 min and then the reaction mixturewas allowed to stir at 90° C. until completion of the reaction. Oncecooled, the mixture was filtered through Celite®. Water was added to thefiltrate and the mixture was partitioned. The aqueous layer wasextracted with ethyl acetate (×3). The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and all volatileswere removed under reduced pressure. The resulting residue was eitherused crude or further purified by flash column chromatography on silicagel (EtOAc/MeOH 100:0 to 90:10) to afford the desired pinacol ester.

General Procedure O

A solution of acid (1.1 eq.), 1-hydroxybenzotriazole hydrate (1.1 eq.)and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.1eq.) in DMF (0.5 M) was stirred at room temperature for 30 min and thentreated with the corresponding amine (1.0 eq.), followed bytriethylamine (5.0 eq.). The reaction mixture was then stirred at roomtemperature for 18 h, poured into brine and extracted with ethylacetate. The organic layer was washed with 0.2 M aq HCl and brine. Theorganic layer was then dried, filtered and the solvent evaporated underreduced pressure to yield the desired crude amide.

General Procedure P

1 M borane THF complex (5.0 eq.) was added dropwise under nitrogen to astirred solution of nitrile derivative (1.0 eq.) in anhydrous THF (0.10M). The reaction mixture was then heated at reflux for 4 h before beingcooled to room temperature. Methanol was added carefully dropwise untilevolution of gas ceased. The solvent was removed under reduced pressureand the residue was dissolved in methanol and treated with conc. aq.HCl. The resultant mixture was heated at reflux for 10 min and thencooled to room temperature. The solvent was removed under reducedpressure and the residue was treated cautiously with excess aq. sodiumbicarbonate solution. The resultant suspension was extracted with ethylacetate and the organic layer was dried, filtered and evaporated underreduced pressure to yield the corresponding amine.

General Procedure Q

To a solution of cobalt (II) chloride (1 eq.) and nitrile derivative (1eq.) in anhydrous MeOH (0.05 M), cooled to 0° C. under a nitrogenatmosphere, was added sodium borohydride (10 eq) portion wise over 10min. The reaction mixture was then stirred for 20 min at 0° C. and thenstirred for a further 60 min at room temperature, quenched with anaqueous solution of ammonium chloride, and allowed to stand overnight.Most of methanol was removed under reduced pressure and the remainingaqueous mixture was diluted with water and washed with Et₂O (×2). Theaqueous layer was basified to pH=12 with 1 M NaOH and extracted withCHCl₃ (×3). The combined organics were dried (phase separator) andconcentrated to give the desired amine.

General Procedure R

A mixture of halide (1 eq.), bis(pinacolato)diboron (1.25 eq.) andpotassium acetate (46 mg, 0.47 mmol) in anhydrous DMSO (0.05 M) wasdegassed with nitrogen for 10 min and then treated with[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloridedichloromethane complex (0.13 eq). The reaction mixture was heated undernitrogen at 120° C. for 30 min and then cooled to room temperature. Themixture was partitioned between ethyl acetate and brine. The organiclayer was washed with brine (×2), dried over sodium sulfate, filteredand concentrated under reduced pressure to yield to the correspondingproduct.

General Procedure S

To a stirred solution of pyrazole-4-carbonitrile (1.0 eq.) andformamidine acetate (10.0 eq.) in ethanol (0.4 M),N,N-diisopropylethylamine (10.0 eq.) was added. The reaction mixture washeated to 110° C. for 16 h. The mixture was cooled to room temperatureand the volatiles removed under reduced pressure. The residue wassuspended in EtOAc and washed with water, a saturated aqueous solutionof ammonium chloride and brine. The organic layer was dried over sodiumsulfate, filtered and concentrated under reduced pressure. Furtherpurification by flash column chromatography on silica gel gave thedesired compound.

5-Amino-1-tert-butyl-pyrazole-4-carbonitrile

To a suspension of tert-butylhydrazine hydrochloride (15.0 g, 120.4mmol) in ethanol (600 mL) was added triethylamine (16.8 mL, 120.4 mmol).The mixture was stirred for 60 min until the hydrazine had dissolved.Ethoxymethylenemalononitrile (14.7 g, 120.4 mmol) was added in portionsand the reaction mixture was heated to 80° C. and stirred at thistemperature overnight. The reaction mixture was concentrated to drynessand the obtained residue was taken up in EtOAc. The organic layer waswashed with water, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The solid was then recrystallized in DCM to afford5-amino-1-tert-butyl-pyrazole-4-carbonitrile (18.6 g, 113.4 mmol, 94%yield) as a light yellow solid.

LC-MS (ES⁺, method 1): 1.36 min, m/z 165.1 [M+H]⁺

1-tert-Butylpyrazolo[3,4-d]pyrimidin-4-amine

A solution of 5-amino-1-tert-butyl-pyrazole-4-carbonitrile (18.0 g, 0.11mol) in formamide (131 mL, 3.29 mol) was stirred at 185° C. overnight.Subsequently, the reaction mixture was cooled to room temperature, waterwas added and the aqueous phase was extracted with EtOAc. The combinedorganics were washed with sat. NaHCO₃ solution, dried over Na₂SO₄,filtered and concentrated in vacuo. The obtained crude product wasrecrystallized in DCM to afford1-tert-butylpyrazolo[3,4-d]pyrimidin-4-amine (12.3 g, 64.3 mmol, 59%yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.04 min, m/z 192.0 [M+H]⁺

3-Bromo-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-4-amine

To a suspension of 1-tert-butylpyrazolo[3,4-d]pyrimidin-4-amine (7.65 g,40.0 mmol) in water (200 mL) was added bromine (4.10 mL, 80.0 mmol)dropwise and the reaction mixture was stirred for 1 h at 100° C. Thereaction mixture was cooled to room temperature and filtered. Theobtained solid was suspended in saturated aqueous Na₂S₂O₃ solution andstirred for 1.5 h. A saturated NaHCO₃ solution was added and theprecipitate was collected by filtration and subsequently washed withEtOAc. The filtrate was washed with water and brine, dried over Na₂SO₄,filtrated and concentrated under reduced pressure. The obtained solidwas recrystallized in DCM to afford3-bromo-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-4-amine (7.74 g, 28.7mmol, 72% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.46 min, m/z 272.0 [M+2]⁺

1-Cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine

Potassium carbonate (4.66 g, 33.71 mmol) and bromocyclopentane (3.6 mL,33.71 mmol) were added to a solution of3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (8.00 g, 30.65 mmol) in DMF(300 mL) at room temperature. The resulting mixture was left to stir at80° C. overnight, diluted with water (500 mL), extracted with DCM (3×300mL), and washed with saturated brine (200 mL) solution. The combinedorganic extracts was dried over Na₂SO₄, filtered and concentrated underreduced pressure. Further purification by flash column chromatography(DCM/MeOH 100:0 to 95:5) followed trituration with methanol afforded1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (2.20 g, 5.90mmol, 19% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.45 min, m/z 330.0 [M+H]⁺

Example 1:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

[4-[[(2-Methoxybenzoyl)amino]methyl]phenyl]boronic Acid

Following general procedure A, 2-methoxybenzoic acid (0.25 mL, 1.76mmol) and [4-(aminomethyl)phenyl]boronic acid hydrochloride (300 mg,1.60 mmol) afforded the title compound (370 mg, 1.3 mmol, 81% yield).

UPLC-MS (ES⁺, Short acidic): 1.31 min, m/z 285.9 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

Following general procedure D,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.24 mmol)and [4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid (104 mg,0.36 mmol) afforded, after purification by mass-directedsemi-preparative HPLC,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide(70 mg, 0.15 mmol, 63% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.55 min, m/z 443.5 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.50 min, m/z 443.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 8.24 (s, 1H), 7.77(dd, J=7.6, 1.9 Hz, 1H), 7.64 (d, J=8.3 Hz, 2H), 7.52-7.47 (m, 3H), 7.17(d, J=7.6 Hz, 1H), 7.05 (t, J=6.8 Hz, 1H), 5.29-5-19 (m, 1H), 4.59 (d,J=6.1 Hz, 2H), 3.92 (s, 3H), 2.15-2.00 (m, 4H), 1.94-1.85 (m, 2H),1.75-1.67 (m, 2H).

Example 2:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-fluoro-benzamide

[4-[[(2-Fluorobenzoyl)amino]methyl]phenyl]boronic Acid

Following general procedure A, 2-fluorobenzoic acid (183 mg, 1.30 mmol)and [4-(aminomethyl)phenyl]boronic acid hydrochloride (269 mg, 1.43mmol) afforded crude [4-[[(2-fluorobenzoyl)amino]methyl]phenyl]boronicacid (237 mg, 0.87 mmol, 67% yield).

UPLC-MS (ES⁺, Short acidic): 1.25 min, m/z 274.1 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-fluoro-benzamide

Following general procedure D,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.24 mmol)and [4-[[(2-fluorobenzoyl)amino]methyl]phenyl]boronic acid (100 mg, 0.36mmol) afforded, after purification by mass-directed semi-preparativeHPLC,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-fluoro-benzamide(29 mg, 0.07 mmol, 28% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.53 min, m/z 431.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.48 min, m/z 431.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.95 (t, J=6.1 Hz, 1H), 8.24 (s, 1H),7.71-7.64 (m, 3H), 7.59-7.50 (m, 3H), 7.35-7.29 (m, 2H), 5.29-5-19 (m,1H), 4.56 (d, J=6.1 Hz, 2H), 2.15-2.00 (m, 4H), 1.95-1.85 (m, 2H),1.74-1.64 (m, 2H).

Example 3:N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2,5-difluoro-benzamide

[4-[[(2,5-Difluorobenzoyl)amino]methyl]phenyl]boronic Acid

Following general procedure B, a mixture of 2,5-difluorobenzoyl chloride(0.75 mL, 6.03 mmol) and [4-(aminomethyl)phenyl]boronic acidhydrochloride (1.03 g, 5.48 mmol) afforded[4-[[(2,5-difluorobenzoyl)amino]methyl]phenyl]boronic acid (1.46 g, 5.03mmol, 92% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.34 min, m/z 292.1 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2,5-difluoro-benzamide

Following general procedure D,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.24 mmol)and [4-[[(2,5-difluorobenzoyl)amino]methyl]phenyl]boronic acid (106 mg,0.36 mmol) afforded, after purification by mass-directedsemi-preparative HPLC,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2,5-difluoro-benzamide(37 mg, 0.08 mmol, 33% yield) as a cream solid.

UPLC-MS (ES⁺, Short acidic): 1.58 min, m/z 449.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.59 min, m/z 449.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 9.05 (t, J=6.0 Hz, 1H), 8.24 (s, 1H), 7.65(d, J=8.3 Hz, 2H), 7.52-7.47 (m, 3H), 7.46-7.37 (m, 2H), 5.28-5.19 (m,1H), 4.56 (d, J=6.0 Hz, 2H), 2.15-2.00 (m, 4H), 1.95-1.85 (m, 2H),1.75-1.64 (m, 2H).

Example 4:N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide

[4-[[(5-Fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic Acid

Following general procedure A, a solution of 5-fluoro-2-methoxybenzoicacid (250 mg, 1.47 mmol) and [4-(aminomethyl)phenyl]boronic acidhydrochloride (303 mg, 1.62 mmol) afforded[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (106mg, 0.36 mmol, 24% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.35 min, m/z 303.8 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure D,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.24 mmol)and [4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid(106 mg, 0.36 mmol) afforded, after additional purification bymass-directed semi-preparative HPLC,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide(19 mg, 0.04 mmol, 17% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.66 min, m/z 461.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.68 min, m/z 461.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.87 (t, J=6.7 Hz, 1H), 8.24 (s, 1H), 7.64(d, J=8.6 Hz, 2H), 7.55-7.52 (m, 1H), 7.51 (d, J=8.6 Hz, 2H), 7.38-7.32(m, 1H), 7.20 (dd, J=9.2, 4.3 Hz, 1H), 5.28-5.19 (m, 1H), 4.59 (d, J=6.7Hz, 2H), 3.91 (s, 3H), 2.15-2.00 (m, 4H), 1.95-1.85 (m, 2H), 1.74-1.64(m, 2H).

Example 5:N-[[4-(4-amino-1-tetrahydrofuran-2-yl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

N-[[4-(4-Amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

Following general procedure D,3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.61 g, 10.0 mmol) and[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid (4.28 g, 15.0mmol) afforded the title compound (286 mg, 0.76 mmol, 8% yield) as alight brown solid.

LC-MS (ES⁺, method 1): 1.14 min, m/z 375.1 [M+H]⁺

N-[[4-(4-Amino-1-tetrahydrofuran-2-yl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

To a solution ofN-[[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide(50 mg, 0.13 mmol) in dihydrofuran (0.5 mL, 6.68 mmol) was addedp-toluenesulfonic acid (12 mg, 0.07 mmol). The reaction mixture wasstirred for 5 minutes and subsequently quenched with water. Thesuspension was extracted into ethyl acetate and washed with water andbrine. The organic phase was dried over Na₂SO₄, filtered andconcentrated in vacuo. Further purification by flash columnchromatography (EtOAc 100%) affordedN-[[4-(4-amino-1-tetrahydrofuran-2-yl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide(8 mg, 0.02 mmol, 13% yield) as a colourless solid.

UPLC-MS (ES⁺, Short acidic): 1.45 min, m/z 445.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.19 min, m/z 445.5 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 8.26 (s, 1H), 7.77(dd, J=7.7, 1.7 Hz, 1H), 7.67-7.61 (m, 2H), 7.51 (d, J=8.5 Hz, 2H),7.50-7.45 (m, 1H), 7.15 (dd, J=8.5, 1.0 Hz, 1H), 7.04 (dt, J=7.7, 1.0Hz, 1H), 6.55 (dd, J=7.0, 3.3 Hz, 1H), 4.58 (d, J=6.1 Hz, 2H), 4.04-3.97(m, 1H), 3.91 (s, 3H), 3.89-3.84 (m, 1H), 2.55 (m, 1H), 2.45-2.30 (m,2H), 2.05-1.99 (m, 1H).

Example 6:N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-(trifluoromethoxy)benzamide

[4-[[[2-(Trifluoromethoxy)benzoyl]amino]methyl]phenyl]boronic Acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acidhydrochloride (300 mg, 1.60 mmol) and 2-(trifluoromethoxy)benzoylchloride (395 mg, 1.76 mmol) gave[4-[[[2-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]boronic acid (421mg, 0.93 mmol, 58% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.39 min, m/z 339.8 [M]

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-(trifluoromethoxy)benzamide

Following general procedure D,[4-[[[2-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]boronic acid (232mg, 0.68 mmol) and 1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine(150 mg, 0.46 mmol) affordedN-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-(trifluoromethoxy)benzamide(5 mg, 0.01 mmol, 2% yield) as a thin film.

UPLC-MS (ES⁺, Short acidic): 1.71 min, m/z 497.1 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.78 min, m/z 497.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 9.06 (t, J=6.2 Hz, 1H), 8.25 (s, 1H),7.65-7.58 (m, 2H), 7.63 (d, J=7.8 Hz, 2H), 7.50 (d, J=7.8 Hz, 2H),7.51-7.44 (m, 2H), 5.27-5.20 (m, 1H), 4.53 (d, J=6.2 Hz, 2H), 2.12-1.95(m, 4H), 1.93-1.83 (m, 2H), 1.73-1.62 (m, 2H)

Example 7:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-ethoxy-benzamide

[4-[[(2-Ethoxybenzoyl)amino]methyl]phenyl]boronic Acid

Following general procedure B, 2-ethoxybenzoyl chloride (0.27 mL, 1.76mmol) and [4-(aminomethyl)phenyl]boronic acid hydrochloride (300 mg,1.60 mmol) afforded crude[4-[[(2-ethoxybenzoyl)amino]methyl]phenyl]boronic acid (472 mg, 1.26mmol, 79% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.40 min, m/z 299.9 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-ethoxy-benzamide

Following general procedure D,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.46mmol) and [4-[[(2-ethoxybenzoyl)amino]methyl]phenyl]boronic acid (205mg, 0.68 mmol) afforded, after further purification by flash columnchromatography (DCM/MeOH 100:0 to 95:5),N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-ethoxy-benzamide(137 mg, 0.27 mmol, 59% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.65 min, m/z 457.5 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.83 min, m/z 457.5 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.66 (t, J=6.0 Hz, 1H), 8.24 (s, 1H), 7.75(dd, J=7.7, 1.8 Hz, 1H), 7.66 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.3 Hz, 2H),7.48-7.44 (m, 1H), 7.15 (d, J=7.7 Hz, 1H), 7.04 (td, J=7.5, 1.0 Hz, 1H),5.23 (m, 1H), 4.60 (d, J=6.0 Hz, 2H), 4.17 (q, J=7.0 Hz, 2H), 2.14-2.00(m, 4H), 1.95-1.85 (m, 2H), 1.74-1.64 (m, 2H), 1.37 (t, J=6.9 Hz, 3H).

Example 8:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-isopropoxy-benzamide

[4-[[(2-Isopropoxybenzoyl)amino]methyl]phenyl]boronic Acid

Following general procedure A, 2-isopropoxybenzoic acid (350 mg, 1.94mmol) and [4-(aminomethyl)phenyl]boronic acid hydrochloride (400 mg,2.14 mmol) afforded crude[4-[[(2-isopropoxybenzoyl)amino]methyl]phenyl]boronic acid (378 mg, 1.03mmol, 53% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.47 min, m/z 313.9 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-isopropoxy-benzamide

Following general procedure D,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.46mmol) and [4-[[(2-isopropoxybenzoyl)amino]methyl]phenyl]boronic acid(214 mg, 0.68 mmol) afforded, after further purification by flash columnchromatography (DCM/MeOH 100:0 to 95:5),N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-isopropoxy-benzamide(69 mg, 0.13 mmol, 29% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.72 min, m/z 471.5 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.99 min, m/z 471.5 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.60 (t, J=6.0 Hz, 1H), 8.24 (s, 1H), 7.76(dd, J=7.6, 1.8 Hz, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H),7.48-7.43 (m, 1H), 7.17 (d, J=8.2 Hz, 1H), 7.03 (td, J=7.6, 1.0 Hz, 1H),5.29-5.18 (m, 1H), 4.81-4.72 (m, 1H), 4.60 (d, J=6.0 Hz, 2H), 2.15-2.00(m, 4H), 1.95-1.85 (m, 2H), 1.74-1.64 (m, 2H), 1.30 (d, J=6.0 Hz, 6H).

Example 9:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-4-chloro-2-methoxy-benzamide

[4-[[(4-Chloro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic Acid

Following general procedure A, 5-fluoro-2-methoxy-benzoic acid (350 mg,1.88 mmol) and [4-(aminomethyl)phenyl]boronic acid hydrochloride (387mg, 2.06 mmol) afforded crude[4-[[(4-chloro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (488mg, 0.99 mmol, 53% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.45 min, m/z 319.8 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-4-chloro-2-methoxy-benzamide

Following general procedure D,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.46mmol) and [4-[[(4-chloro-2-methoxy-benzoyl)amino]methyl]phenyl]boronicacid (218 mg, 0.68 mmol) afforded, after further purification by flashcolumn chromatography (DCM/MeOH 100:0 to 95:5),N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-4-chloro-2-methoxy-benzamide(150 mg, 0.28 mmol, 62% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.67 min, m/z 477.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.91 min, m/z 477.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.0 Hz, 1H), 8.24 (s, 1H), 7.76(d, J=8.3, 1H), 7.64 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.2 Hz, 2H), 7.26 (d,J=1.9, 1H), 7.11 (dd, J=8.3, 1.9 Hz, 1H), 5.23 (m, 1H), 4.57 (d, J=6.0Hz, 2H), 3.94 (s, 3H), 2.14-2.00 (m, 4H), 1.94-1.84 (m, 2H), 1.74-1.64(m, 2H).

Example 10:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-4-methyl-benzamide

[4-[[(2-Methoxy-4-methyl-benzoyl)amino]methyl]phenyl]boronic Acid

Following general procedure A, 2-methoxy-4-methylbenzoic acid (300 mg,1.81 mmol) and [4-(aminomethyl)phenyl]boronic acid hydrochloride (372mg, 1.99 mmol) afforded crude[4-[[(2-methoxy-4-methyl-benzoyl)amino]methyl]phenyl]boronic acid (379mg, 1.01 mmol, 56% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.41 min, m/z 300.0 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-4-methyl-benzamide

Following general procedure D,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.46mmol) and [4-[[(2-methoxy-4-methyl-benzoyl)amino]methyl]phenyl]boronicacid (205 mg, 0.68 mmol) afforded, after further purification by flashcolumn chromatography (DCM/MeOH 100:0 to 95:5) and SCX,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-4-methyl-benzamide(111 mg, 0.22 mmol, 48% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.63 min, m/z 457.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.79 min, m/z 457.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.69 (t, J=6.1 Hz, 1H), 8.24 (s, 1H), 7.73(d, J=7.8, 1H), 7.64 (d, J=8.3 Hz, 2H), 7.50 (d, J=8.3 Hz, 2H), 6.99 (s,1H), 6.86 (d, J=7.8, 1.9 Hz, 1H), 5.29-5.19 (m, 1H), 4.58 (d, J=6.1 Hz,2H), 3.91 (s, 3H), 2.36 (s, 3H), 2.14-2.00 (m, 4H), 1.94-1.84 (m, 2H),1.74-1.64 (m, 2H).

Example 11:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-5-chloro-2-methoxy-benzamide

4-[[(5-Chloro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic Acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acidhydrochloride (387 mg, 2.06 mmol) and 5-chloro-2-methoxybenzoic acid(350 mg, 1.88 mmol) gave[4-[[(5-chloro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (259mg, 0.53 mmol, 28% yield as a yellow oil.

UPLC-MS (ES⁺, Short acidic): 1.45 min, m/z 319.8 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-5-chloro-2-methoxy-benzamide

Following general procedure D,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.24 mmol)and [4-[[(5-chloro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid(117 mg, 0.36 mmol) gave, after further purification by flash columnchromatography, eluting with 0-10% MeOH in EtOAc,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-5-chloro-2-methoxy-benzamide(50 mg, 0.10 mmol, 41% yield) as a cream solid.

UPLC-MS (ES⁺, Short acidic): 1.66 min, m/z 477.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.83 min, m/z 477.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.85 (t, J=6.1 Hz, 1H), 8.24 (s, 1H), 7.70(d, J=2.8 Hz, 1H), 7.66-7.61 (m, 2H), 7.53 (dd, J=8.8, 2.8 Hz, 1H),7.52-7.47 (m, 2H), 7.20 (d, J=8.8 Hz, 1H), 5.27-5.18 (m, 1H), 4.57 (d,J=6.1 Hz, 2H), 3.91 (s, 3H), 2.15-1.97 (m, 4H), 1.94-1.83 (m, 2H),1.75-1.62 (m, 2H).

Example 12:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-5-methyl-benzamide

[4-[[(2-Methoxy-5-methyl-benzoyl)amino]methyl]phenyl]boronic Acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acidhydrochloride (434 mg, 2.32 mmol) and 5-fluoro-2-methoxy-benzoic acid(350 mg, 2.06 mmol) gave[4-[[(2-methoxy-5-methyl-benzoyl)amino]methyl]phenyl]boronic acid (215mg, 0.36 mmol, 17% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.40 min, m/z 299.9 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-5-methyl-benzamide

Following general procedure D,[4-[[(2-methoxy-5-methyl-benzoyl)amino]methyl]phenyl]boronic acid (136mg, 0.46 mmol) and 1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine(100 mg, 0.30 mmol) affordedN-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-5-methyl-benzamide(22 mg, 0.05 mmol, 15% yield) as a crystalline off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.66 min, m/z 477.2 [M+Na]⁺

UPLC-MS (ES⁺, Long acidic): 3.74 min, m/z 457.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.74 (t, J=6.1 Hz, 1H), 8.23 (s, 1H),7.66-7.61 (m, 2H), 7.60-7.57 (m, 1H), 7.52-7.47 (m, 2H), 7.31-7.26 (m,1H), 7.05 (d, J=8.4 Hz, 1H), 5.27-5.18 (m, 1H), 4.57 (d, J=6.1 Hz, 2H),3.88 (s, 3H), 2.28 (s, 3H), 2.15-1.97 (m, 4H), 1.94-1.82 (m, 2H),1.74-1.62 (m, 2H).

Example 13:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-5-(trifluoromethyl)benzamide

[4-[[[2-Methoxy-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicAcid

Following general procedure B, [4-(aminomethyl)phenyl]boronic acidhydrochloride (300 mg, 1.60 mmol) and2-methoxy-5-(trifluoromethyl)benzoyl chloride (420 mg, 1.76 mmol) gave[4-[[[2-methoxy-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (559 mg, 1.34 mmol, 84% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.51 min, m/z 353.9 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-5-(trifluoromethyl)benzamide

Following general procedure D,[4-[[[2-methoxy-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (161 mg, 0.46 mmol) and1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.30mmol) gaveN-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-5-(trifluoromethyl)benzamide(78 mg, 0.14 mmol, 45% yield) as a cream solid.

UPLC-MS (ES⁺, Short acidic): 1.71 min, m/z 511.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.95 min, m/z 511.4 [M+H]⁺

¹H NMR (400 MHz, CDCl₃, δ): 8.56 (d, J=2.3 Hz, 1H), 8.37 (s, 1H),8.21-8.14 (m, 1H), 7.76-7.71 (m, 1H), 7.71-7.66 (m, 2H), 7.55-7.49 (m,2H), 7.12-7.07 (m, 1H), 5.45-5.38 (m, 2H), 5.36-5.27 (m, 1H), 4.77 (d,J=5.9 Hz, 2H), 4.03 (s, 3H), 2.23-2.13 (m, 4H), 2.02-1.92 (m, 2H),1.79-1.67 (m, 2H).

Example 14:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-3-fluoro-2-methoxy-benzamide

[4-[[(3-Fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic Acid

Following general procedure A, 3-fluoro-2-methoxybenzoic acid (300 mg,1.76 mmol) and [4-(aminomethyl)phenyl]boronic acid hydrochloride (364mg, 1.94 mmol) afforded crude[4-[[(3-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (382mg, 0.88 mmol, 50% yield) as a brown solid

UPLC-MS: UPLC-MS (ES⁺, Short acidic): 1.37 min, m/z 304.0 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-3-fluoro-2-methoxy-benzamide

Following general procedure D,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.30mmol) and [4-[[(3-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronicacid (138 mg, 0.46 mmol) afforded, after further purification by flashcolumn chromatography (DCM/MeOH 100:0 to 95:5) and SCX,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-3-fluoro-2-methoxy-benzamide(83 mg, 0.16 mmol, 53% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.59 min, m/z 461.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.65 min, m/z 461.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.89 (t, J=6.1 Hz, 1H), 8.24 (s, 1H), 7.65(d, J=8.2, 2H), 7.52 (d, J=8.2 Hz, 2H), 7.43-7.38 (m, 2H), 7.22-7.17 (m,1H), 5.23 (m, 1H), 4.57 (d, J=6.1 Hz, 2H), 3.91 (d, J=1.6 Hz, 3H),2.14-2.00 (m, 4H), 1.94-1.84 (m, 2H), 1.74-1.64 (m, 2H).

Example 15:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-4-fluoro-2-methoxy-benzamide

[4-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic Acid

Following general procedure A, 4-fluoro-2-methoxybenzoic acid (300 mg,1.76 mmol) and [4-(aminomethyl)phenyl]boronic acid hydrochloride (364mg, 1.94 mmol) afforded crude[4-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (399mg, 1.18 mmol, 67% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.36 min, m/z 303.9 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-4-fluoro-2-methoxy-benzamide

Following general procedure D,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.30mmol) and [4-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronicacid (138 mg, 0.46 mmol) afforded, after further purification by flashcolumn chromatography (DCM/MeOH 100:0 to 95:5) and SCX,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-4-fluoro-2-methoxy-benzamide(83 mg, 0.16 mmol, 53% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.59 min, m/z 461.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.63 min, m/z 461.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.73 (t, J=6.1 Hz, 1H), 8.24 (s, 1H),7.86-7.82 (m, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 7.09(dd, J=11.4, 2.4 Hz, 1H), 6.88 (td, J=8.4, 2.4 Hz, 1H), 5.23 (m, 1H),4.58 (d, J=6.1 Hz, 2H), 3.94 (s, 3H), 2.14-2.00 (m, 4H), 1.94-1.84 (m,2H), 1.74-1.64 (m, 2H).

Example 16:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-fluoro-6-methoxy-benzamide

[4-[[(2-Fluoro-6-methoxy-benzoyl)amino]methyl]phenyl]boronic Acid

Following procedure B, 2-fluoro-6-methoxybenzoyl chloride (0.21 mL, 1.47mmol) and 4-aminomethylphenylboronic acid hydrochloride (250 mg, 1.33mmol) gave crude[4-[[(2-fluoro-6-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (447mg, 0.74 mmol, 55% yield) as a yellow solid.

LC-MS (ES⁺, Short acidic): 2.85 min, m/z 304 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-fluoro-6-methoxy-benzamide

Following general procedure D,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (73 mg, 0.22 mmol)and [4-[[(2-fluoro-6-methoxy-benzoyl)amino]methyl]phenyl]boronic acid(201 mg, 0.33 mmol) gaveN-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-fluoro-6-methoxy-benzamide(71 mg, 0.15 mmol, 70% yield).

UPLC-MS: (ES⁺, Short acidic): 1.47 min, m/z 461.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.36 min, m/z 461.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.99 (t, J=6.4 Hz, 1H), 8.24 (s, 1H), 7.65(d, J=8.2 Hz, 2H), 7.52 (d, J=8.2 Hz, 2H), 7.42-7.40 (m, 1H), 6.95 (d,J=8.2 Hz, 1H), 6.87 (t, J=8.6 Hz, 1H), 5.28-5.20 (m, 1H), 4.53 (d, J=6.4Hz, 2H), 3.84 (s, 3H), 2.11-2.04 (m, 4H), 1.93-1.89 (m, 2H), 1.72-1.68(m, 2H).

Example 17:N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-N-methyl-benzamide

[4-[[(2-Methoxybenzoyl)-methyl-amino]methyl]phenyl]boronic acid

[4-[[(2-Methoxybenzoyl)amino]methyl]phenyl]boronic acid (30 mg, 0.11mmol) was dissolved in DMF (1 mL). Sodium hydride (42 mg, 1.05 mmol) wasadded and the reaction mixture stirred for 30 minutes before iodomethane(0.33 mL, 0.53 mmol) was added. The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was quenched with ammoniumchloride and extracted with EtOAc. The combined organic phase was driedover sodium sulfate and reduced under reduced pressure to give[4-[[(2-methoxybenzoyl)-methyl-amino]methyl]phenyl]boronic acid (49 mg,0.11 mmol, assumed quantitative).

LC-MS (ES⁺, method 1): 3.08 min, m/z 300.1 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-N-methyl-benzamide

Following the general procedure D,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (15 mg, 0.05 mmol)and [4-[[(2-methoxybenzoyl)-methyl-amino]methyl]phenyl]boronic acid (41mg, 0.07 mmol) gaveN-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-N-methyl-benzamide(17 mg, 0.03 mmol, 71% yield) as a white solid.

LC-MS (ES⁺, method 1): 3.29 min, m/z 457.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.67 min, m/z 457.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ) (mixture of rotamers): 8.24 (s, 0.6H), 8.239 (s, 0.4H), 7.71-7.59 (m, 1H), 7.53-7.20 (m, 5H), 7.15-6.95 (3H),5.29-5.18 (m, 1H), 4.99-4.51 (m, 1.2H), 4.38 (s, 0.8H), (3.85 (5, 1.8H),3.81 (s, 1.2H), 2.92 (s, 1.2H), 2.72 (5, 1.8H), 2.15-1.97 (m, 4H),1.95-1.83 (m, 2H), 1.75-1.61 (m, 2H).

Example 18:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-pyridine-3-carboxamide

4-[[(2-Methoxypyridine-3-carbonyl)amino]methyl]phenyl]boronic Acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acidhydrochloride (404 mg, 2.15 mmol) and 2-methoxy-nicotinic acid (300 mg,1.96 mmol) afforded crude[4-[[(2-methoxypyridine-3-carbonyl)amino]methyl]phenyl]boronic acid (287mg, 0.80 mmol, 41% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.20 min, m/z 287.0 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-pyridine-3-carboxamide

Following general procedure D,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.30mmol) and [4-[[(2-methoxypyridine-3-carbonyl)amino]methyl]phenyl]boronicacid (130 mg, 0.46 mmol) afforded, after further purification by flashcolumn chromatography on silica gel (DCM/MeOH 100:0 to 95:5),N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-pyridine-3-carboxamide(87 mg, 0.18 mmol, 58% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.49 min, m/z 444.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.46 min, m/z 444.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.87 (t, J=6.1 Hz, 1H), 8.32 (dd, J=4.9,2.0 Hz, 1H), 8.24 (s, 1H), 8.17 (dd, J=7.4, 2.0 Hz, 1H), 7.64 (d, J=8.2Hz, 2H), 7.51 (d, J=8.3 Hz, 2H), 7.14 (dd, J=7.4, 4.9 Hz, 1H), 5.23 (m,1H), 4.59 (d, J=6.1 Hz, 2H), 4.00 (s, 3H), 2.14-2.00 (m, 4H), 1.94-1.84(m, 2H), 1.74-1.64 (m, 2H).

Example 19:N-[[4-[4-amino-1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

1,4-Dioxaspiro[4.5]decan-8-ol

To a solution of 1,4-cyclohexanedione monoethylene acetal (2.0 g, 12.81mmol) in methanol (25 mL), cooled to 0° C., was added sodium borohydride(0.5 g, 14.09 mmol). After 30 min of stirring at room temperature, asaturated solution of aqueous NH₄Cl (20 mL) was added carefully. Theaqueous layer was extracted with DCM (3×20 mL) and the combined organicextracts were filtered over a phase separator, concentrated underreduced pressure to give the crude 1,4-dioxaspiro[4.5]decan-8-ol (2.0 g,12.81 mmol, 100% yield) as a colourless oil.

¹H NMR (400 MHz, CDCl₃, δ): 3.96-3.88 (m, 4H), 3.83-3.73 (m, 1H),1.92-1.75 (m, 4H), 1.70-1.51 (m, 4H), 1.31 (d, J=3.1 Hz, 1H).

1,4-Dioxaspiro[4.5]decan-8-yl methanesulfonate

Following general procedure L, 1,4-dioxaspiro[4.5]decan-8-ol (400 mg,2.53 mmol) gave 1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (598 mg,2.53 mmol, assumed quantitative) as a colourless solid

¹H NMR (400 MHz, CDCl₃, δ): 4.82-4.74 (m, 1H), 3.93-3.83 (m, 4H), 2.95(s, 3H), 2.00-1.86 (m, 4H), 1.86-1.73 (m, 2H), 1.63-1.52 (m, 2H)

1-(1,4-Dioxaspiro[4.5]decan-8-yl)-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine

Following general procedure M, 1,4-dioxaspiro[4.5]decan-8-ylmethanesulfonate (592 mg, 2.51 mmol) and3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330 mg, 1.26 mmol) gave1-(1,4-dioxaspiro[4.5]decan-8-yl)-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine(100 mg, 0.24 mmol, 19% yield) as a yellow-white solid.

LC-MS (ES⁺, Method 1): 2.80 min, m/z 402.0 [M+H]⁺

N-[[4-[4-Amino-1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure C,1-(1,4-dioxaspiro[4.5]decan-8-yl)-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine(280 mg, 0.70 mmol) and[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid (279 mg, 0.98mmol) gaveN-[[4-[4-amino-1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(182 mg, 0.34 mmol, 48% yield) as an off-white powder.

UPLC-MS (ES⁺, Long acidic): 3.27 min, m/z 515.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.2 Hz, 1H), 8.24 (s, 1H), 7.77(dd, J=7.6, 1.8 Hz, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.54-7.45 (m, 3H), 7.17(d, J=7.2 Hz, 1H), 7.05 (dt, J=7.6, 0.8 Hz, 1H), 4.85-4.73 (m, 1H), 4.59(d, J=6.2 Hz, 2H), 3.96-3.86 (m, 7H), 2.31-2.18 (m, 2H), 1.95-1.70 (m,6H)

Example 20:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-3-cyano-benzamide

[4-[[(3-Cyanobenzoyl)amino]methyl]phenyl]boronic Acid

Following general procedure A, 4-(aminomethyl)phenyl]boronic acidhydrochloride (350 mg, 1.87 mmol) and 3-cyanobenzoic acid (250 mg, 1.70mmol) afforded crude [4-[[(3-cyanobenzoyl)amino]methyl]phenyl]boronicacid (284 mg, 0.86 mmol, 51% yield) as a brown solid.

LC-MS (ES⁺, Method 1): 3.06 min, m/z 281.0 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-3-cyano-benzamide

Following general procedure C,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.30mmol) and [4-[[(3-cyanobenzoyl)amino]methyl]phenyl]boronic acid (128 mg,0.46 mmol) gaveN-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-3-cyano-benzamide(81 mg, 0.17 mmol, 58% yield) as an off-white solid.

UPLC-MS (ES⁺, Long acidic): 3.39 min, m/z 438.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 9.32 (t, J=5.9 Hz, 1H), 8.37-8.32 (m, 1H),8.25-8.20 (m, 2H), 8.06-8.01 (m, 1H), 7.73 (t, J=8.2 Hz, 1H), 7.64 (d,J=8.2 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 5.23 (quint, J=7.4 Hz, 1H), 4.58(d, J=5.9 Hz, 2H), 2.15-1.97 (m, 4H), 1.96-1.82 (m, 2H), 1.75-1.62 (m,2H)

Example 21:N-[[4-[4-amino-1-(3-oxocyclopentyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

3-(4-Amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopentanone

At room temperature, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL, 1.53mmol) was added slowly dropwise to a suspension of3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (800 mg, 3.06 mmol) and2-cyclopentenone (0.31 mL, 3.68 mmol) in MeCN (6 mL). After allowing thereaction mixture to stir at room temperature overnight, silica was addedand all volatiles were removed under reduced pressure. Furtherpurification by flash column chromatography on silica gel (DCM/MeOH100:0 to 92:8) afforded3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopentanone (361 mg,1.05 mmol, 34% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 2.69 min, m/z 344.0 [M+H]⁺

N-[[4-[4-Amino-1-(3-oxocyclopentyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure C,3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopentanone (80.0 mg,0.23 mmol) and [4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid(100 mg, 0.35 mmol) gaveN-[[4-[4-amino-1-(3-oxocyclopentyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(31.7 mg, 0.06 mmol, 28% yield) as a brown solid.

LC-MS (ES⁺, Method 1): 2.82 min, m/z 457.1 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.98 min, m/z 457.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.0 Hz, 1H), 8.27 (s, 1H), 7.77(dd, J=7.6, 1.8 Hz, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H),7.51-7.45 (m, 1H), 7.17 (d, J=8.2 Hz, 1H), 7.05 (t, J=7.6 Hz, 1H),5.64-5.55 (m, 1H), 4.59 (d, J=6.0 Hz, 2H), 3.91 (s, 3H), 2.86-2.65 (m,2H), 2.50-2.26 (m, 4H)

Example 22:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-3-methyl-benzamide

[4-[[(2-Methoxy-3-methyl-benzoyl)amino]methyl]phenyl]boronic Acid

Following general procedure A, 4-(aminomethyl)phenyl]boronic acidhydrochloride (248 mg, 1.32 mmol) and 2-methoxy-3-methylbenzoic acid(200 mg, 1.20 mmol) afforded crude[4-[[(2-methoxy-3-methyl-benzoyl)amino]methyl]phenyl]boronic acid (213mg, 0.61 mmol, 50% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.37 min, m/z 299.8 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-3-methyl-benzamide

Following general procedure C,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.30mmol) and [4-[[(2-methoxy-3-methyl-benzoyl)amino]methyl]phenyl]boronicacid (136 mg, 0.46 mmol) gaveN-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-3-methyl-benzamide(116 mg, 0.24 mmol, 80% yield) as a pink solid.

UPLC-MS (ES⁺, Short acidic): 1.61 min, m/z 457.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.77 min, m/z 457.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.82 (t, J=6.0 Hz, 1H), 8.24 (s, 1H), 7.65(d, J=8.1 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.45-7.38 (m, 1H), 7.37-7.30(m, 1H), 7.10 (t, J=7.6 Hz, 1H), 5.23 (quint, J=7.4 Hz, 1H), 4.55 (d,J=6.1 Hz, 2H), 3.71 (s, 3H), 2.28 (s, 3H), 2.17-1.96 (m, 4H), 1.96-1.81(m, 2H), 1.76-1.61 (m, 2H)

Example 23:N-[[4-[4-amino-1-(4-hydroxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

N-[[4-[4-Amino-1-(4-hydroxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

To a solution ofN-[[4-[4-amino-1-(4-oxocyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(120 mg, 0.26 mmol) in methanol (1 mL), cooled to 0° C., was addedsodium borohydride (11 mg, 0.28 mmol). The reaction mixture was stirredat 70° C. overnight, cooled and then carefully quenched with a saturatedsolution of aqueous NH₄Cl (20 mL). The aqueous layer was extracted withDCM (3×10 mL) and the combined organic extracts were filtered over aphase separator, concentrated under reduced pressure to give the crudealcohol. Further purification by flash column chromatography on silicagel (DCM/MeOH 100:0 to 95:5) afforded isomer 1 (43 mg, 0.09 mmol, 34%yield, isomer 1) as a white solid and isomer 2 (34 mg, 0.07 mmol, 26%yield, isomer 2) as a white solid.

UPLC-MS (ES⁺, Short acidic, isomer 1): 1.24 min, m/z 473.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic, isomer 1): 2.82 min, m/z 473.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ, isomer 1): 8.77 (t, J=6.1 Hz, 1H), 8.23 (s,1H), 7.78 (dd, J=7.6, 1.8 Hz, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.53-7.46 (m,3H), 7.17 (d, J=8.3 Hz, 1H), 7.05 (t, J=7.4 Hz, 1H), 4.75-4.64 (m, 1H),4.59 (d, J=6.1 Hz, 2H), 4.48 (d, J=2.6 Hz, 1H), 3.92 (s, 3H), 3.90 (s,1H), 2.44-2.29 (m, 2H), 1.88-1.76 (m, 2H), 1.72-1.56 (m, 4H)

UPLC-MS (ES⁺, Long acidic, isomer 2): 2.79 min, m/z 473.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ, isomer 2): 8.77 (t, J=6.0 Hz, 1H), 8.24 (s,1H), 7.77 (dd, J=7.6, 1.8 Hz, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.54-7.45 (m,3H), 7.17 (d, J=8.2 Hz, 1H), 7.08-7.02 (m, 1H), 4.69 (d, J=4.4 Hz, 1H),4.68-4.59 (m, 1H), 4.59 (d, J=6.1 Hz, 2H), 3.92 (s, 3H), 3.61-3.48 (m,1H), 2.11-1.84 (m, 6H), 1.50-1.34 (m, 2H)

Example 24:N-[[4-[4-amino-1-[(1R*,3S*)-3-hydroxycyclopentyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

N-[[4-[4-Amino-1-[(1R*,3S*)-3-hydroxycyclopentyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

To a solution ofN-[[4-[4-amino-1-(3-oxocyclopentyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(60 mg, 0.13 mmol) in methanol (0.80 mL), cooled and then carefullyquenched with a saturated solution of aqueous NH₄Cl (20 mL). The aqueouslayer was extracted with DCM (3×10 mL) and the combined organic extractswere filtered over a phase separator, concentrated under reducedpressure to give the crude alcohol. Further purification by flash columnchromatography on silica gel (DCM/MeOH 100:0 to 95:5) affordedN-[[4-[4-amino-1-[(1R*,3S*)-3-hydroxycyclopentyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(20 mg, 0.04 mmol, 34% yield) as an off-white solid

UPLC-MS (ES⁺, Long acidic): 2.86 min, m/z 459.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.2 Hz, 1H), 8.24 (s, 1H), 7.77(dd, J=7.6, 2.0 Hz, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.55-7.46 (m, 3H), 7.17(d, J=7.7 Hz, 1H), 7.05 (dt, J=7.5, 0.9 Hz, 1H), 5.18 (quint, J=8.2 Hz,1H), 4.95 (d, J=5.0 Hz, 1H), 4.59 (d, J=6.2 Hz, 2H), 4.29-4.15 (m, 1H),3.92 (s, 3H), 2.46-2.31 (m, 1H), 2.25-2.12 (m, 1H), 2.12-1.70 (m, 4H)

Example 25:N-[[4-[4-amino-1-(1,4-dioxaspiro[4.4]nonan-8-yl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

1-(1,4-Dioxaspiro[4.4]nonan-8-yl)-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine

At room temperature and under an atmosphere of nitrogen, a mixture of3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)cyclopentanone (270 mg,0.79 mmol), ethylene glycol (0.18 mL, 3.15 mmol), p-toluenesulfonic acidmonohydrate (15 mg, 0.08 mmol) and anhydrous trimethyl orthoformate(0.17 mL, 1.57 mmol) in DCM (2 mL) was heated to 80° C. and stirredovernight. The mixture was cooled and additional ethylene glycol (0.18mL, 3.15 mmol) and anhydrous trimethyl orthoformate (0.17 mL, 1.57 mmol)were added. The mixture was heated to 90° C. and stirred overnight. Themixture was cooled and additional ethylene glycol (0.36 mL, 6.30 mmol)and anhydrous trimethyl orthoformate (0.34 mL, 3.14 mmol) were added.After 72 h at 90° C., the reaction was carefully quenched with asaturated solution of ammonium chloride. Water (15 mL) and DCM (15 mL)were then added. The aqueous layer was extracted with DCM (2×20 mL) andthe combined organic extracts were filtered over a phase separator andconcentrated under reduced pressure. Further purification by flashcolumn chromatography on silica gel (DCM/MeOH 100:0 to 96:4) afforded1-(1,4-dioxaspiro[4.4]nonan-8-yl)-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine(221 mg, 0.57 mmol, 73% yield) as an off-white solid

UPLC-MS (ES⁺, Short acidic): 1.22 min, m/z 388.0 [M+H]⁺

N-[[4-[4-Amino-1-(1,4-dioxaspiro[4.4]nonan-8-yl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure C,1-(1,4-dioxaspiro[4.4]nonan-8-yl)-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine(176 mg, 0.45 mmol) and[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid (168 mg, 0.59mmol) gaveN-[[4-[4-amino-1-(1,4-dioxaspiro[4.4]nonan-8-yl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(220 mg, 0.42 mmol, 92% yield) as an orange solid.

UPLC-MS (ES⁺, Long acidic): 3.20 min, m/z 501.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 8.25 (s, 1H), 7.78(dd, J=7.6, 1.6 Hz, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.55-7.45 (m, 3H), 7.17(d, J=8.3 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 5.25 (quint, J=8.2 Hz, 1H),4.59 (d, J=6.1 Hz, 2H), 3.97-3.81 (m, 7H), 2.44-2.26 (m, 2H), 2.24-2.07(m, 3H), 2.05-1.79 (m, 1H)

Example 26:N-[[4-[4-amino-1-(4-oxocyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

N-[[4-[4-Amino-1-(4-oxocyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Under an atmosphere of nitrogen and at 0° C., trifluoromethanesulfonicacid (0.28 mL, 3.11 mmol) was added to a suspension ofN-[[4-[4-amino-1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(80 mg, 0.16 mmol) in DCM (0.75 mL) and water (0.08 mL). The reactionmixture was allowed to return to room temperature and stirred overnight,then carefully quenched with a saturated solution of NaHCO₃. The aqueouslayer was extracted with DCM (3×10 mL). The combined organic extractswere filtered over a phase separator and concentrated under reducedpressure. Further purification by flash column chromatography on silicagel (DCM/MeOH 100:0 to 96:4) affordedN-[[4-[4-amino-1-(4-oxocyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(70 mg, 0.15 mmol, 96% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.45 min, m/z 471.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.98 min, m/z 471.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 8.28 (s, 1H), 7.77(dd, J=7.6, 1.6 Hz, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.56-7.45 (m, 3H), 7.17(d, J=8.4 Hz, 1H), 7.05 (t, J=7.7 Hz, 1H), 5.31-5.20 (m, 1H), 4.59 (d,J=6.1 Hz, 2H), 3.92 (s, 3H), 2.80-2.63 (m, 2H), 2.46-2.31 (m, 4H),2.31-2.17 (m, 2H)

Example 27:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-4-methoxy-pyridine-3-carboxamide

N-[(4-Bromophenyl)methyl]-4-methoxy-pyridine-3-carboxamide

Following general procedure F, a mixture of 4-methoxynicotinic acid (150mg, 0.98 mmol) and 4-bromobenzylamine hydrochloride (240 mg, 1.08 mmol)afforded crudeN-[(4-bromophenyl)methyl]-4-methoxy-pyridine-3-carboxamide (200 mg, 0.53mmol, 54% yield) as a clear oil which was used directly in the nextstep.

LC-MS (ES⁺, Method 1): 2.49 min, m/z 321.0 [M]⁺

4-Methoxy-N-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyridine-3-carboxamide

Following general procedure N,N-[(4-bromophenyl)methyl]-4-methoxy-pyridine-3-carboxamide (200 mg, 0.62mmol) afforded, after further purified by flash column chromatography onsilica gel (EtOAc/MeOH 100:0 to 90:10),4-methoxy-N-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyridine-3-carboxamide(125 mg, 0.34 mmol, 54% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1.35 min, m/z 368.9 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-4-methoxy-pyridine-3-carboxamide

Following general procedure C,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (90 mg, 0.27 mmol)and4-methoxy-N-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyridine-3-carboxamide(126 mg, 0.34 mmol) gaveN-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-4-methoxy-pyridine-3-carboxamide(83 mg, 0.18 mmol, 65% yield) as an off-white solid.

UPLC-MS (ES⁺, Long acidic): 2.60 min, m/z 444.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.82 (t, J=6.1 Hz, 1H), 8.71 (s, 1H), 8.55(d, J=5.8 Hz, 1H), 8.24 (s, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.2Hz, 2H), 7.21 (d, J=5.9 Hz, 1H), 5.24 (quint, J=7.4 Hz, 1H), 4.58 (d,J=6.1 Hz, 2H), 3.97 (s, 3H), 2.18-1.96 (m, 4H), 1.96-1.81 (m, 2H),1.76-1.61 (m, 2H)

Example 28:N-[[4-[4-amino-1-[4-(methylamino)cyclohexyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

N-[[4-[4-Amino-1-[4-(methylamino)cyclohexyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

To a solution of 2 M methylamine in THF (0.05 mL, 0.11 mmol) andN-[[4-[4-amino-1-(4-oxocyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(50 mg, 0.11 mmol) in DCM (0.30 mL) was added acetic acid (0.05 mL). Thereaction mixture was stirred for 30 min, then sodiumtriacetoxyborohydride (32 mg, 0.15 mmol) was added. The reaction mixturewas then stirred for 1 h, quenched with a 1 M aqueous solution of NaOH(5 mL). The aqueous layer was extracted with DCM (3×10 mL). The combinedorganic extracts were filtered over a phase separator and concentratedunder reduced pressure. Further purification by flash columnchromatography on silica gel (DCM/MeOH 94:6 to 0:100) affordedN-[[4-[4-amino-1-[4-(methylamino)cyclohexyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(28 mg, 0.06 mmol, 54% yield) as a white solid.

LC-MS (ES⁺, Method 1): 2.46 min, m/z 486.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.43 min, m/z 486.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ) (2:1 mixture of conformers): 8.77 (t, J=6.1Hz, 1H), 8.25-8.22 (m, 1H), 7.78 (dd, J=7.6, 1.6 Hz, 1H), 7.68-7.61 (m,2H), 7.54-7.46 (m, 3H), 7.17 (d, J=8.3 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H),4.78-4.61 (m, 1H), 4.59 (d, J=4.6 Hz, 2H), 3.92 (s, 3H), 2.70-2.63 (m,1H), 2.50-2.31 (m, 1H), 2.31 (s, 1H), 2.28 (s, 2H), 2.11-1.90 (m, 2.7H),1.90-1.78 (m, 1.3H), 1.70-1.55 (m, 3H).

Example 29:N-[[4-(4-amino-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

Tetrahydropyran-4-yl methanesulfonate

Following general procedure L, tetrahydro-2H-pyran-4-ol (0.97 mL, 8.81mmol) afforded tetrahydropyran-4-yl methanesulfonate (1.60 g, 7.77 mmol,88% yield) as a colourless oil.

¹H NMR (400 MHz, CDCl₃, δ): 4.91 (m, 1H), 3.98-3.92 (m, 2H), 3.58-3.52(m, 2H), 3.05 (s, 3H), 2.09-2.02 (m, 2H), 1.93-1.84 (m, 2H).

3-Iodo-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-amine

Following general procedure M,3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.00 g, 3.83 mmol) andtetrahydropyran-4-yl methanesulfonate (1.38 g, 7.67 mmol) afforded,after further purification by flash column chromatography on silica gel(DCM/MeOH 100:0 to 90:10),3-iodo-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-amine (0.49 g,1.26 mmol, 33% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.09 min, m/z 345.9 [M+H]⁺

N-[[4-(4-Amino-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

Following general procedure D,3-iodo-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg,0.43 mmol) and [4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid(186 mg, 0.65 mmol) afforded, after further purification by flash columnchromatography on silica gel (DCM/MeOH 100:0 to 95:5),N-[[4-(4-amino-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide(109 mg, 0.21 mmol, 49% yield) as a red-orange solid.

UPLC-MS (ES⁺, Short acidic): 1.31 min, m/z 459.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.97 min, m/z 459.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 8.25 (s, 1H), 7.77(dd, J=7.6, 1.8 Hz, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.52-7.47 (m, 3H), 7.17(d, J=8.2 Hz, 1H), 7.05 (td, J=14.0, 1.0 Hz, 1H), 5.00-4.94 (m, 1H),4.59 (d, J=6.1 Hz, 2H), 4.01 (dd, J=10.2, 3.4 Hz, 2H), 3.92 (s, 3H),3.55 (t, J=11.1 Hz, 2H), 2.26-2.16 (m, 2H), 1.89 (d, J=10.2 Hz, 2H).

Example 30:4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanecarboxylicacid

4-[4-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanecarboxylicacid

To a solution of ethyl4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanecarboxylate(300 mg, 0.57 mmol) in THF (2 mL) and water (2 mL) was added sodiumhydroxide (136 mg, 3.41 mmol) and the resulting mixture was stirredovernight. Additional sodium hydroxide (136 mg, 3.41 mmol) was added andthe reaction mixture was allowed to stir at 70° C. for 72 h, cooled toroom temperature, and then acidified to pH 3 with 1 M HCl. The mixturewas partitioned between DCM (10 mL) and H₂O (10 mL). The aqueous layerwas then extracted with DCM (3×20 mL). The combined organic extractswere then passed through a phase separator and concentrated underreduced pressure. The crude product was further purified by flash columnchromatography on silica gel (DCM/MeOH 100:0 to 95:5) to afford4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanecarboxylicacid (229 mg, 0.46 mmol, 81% yield) as an off-white solid.

LC-MS (ES⁺, Method 1): 2.90 min, m/z 501.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.94 min, m/z 501.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ) (1:1 mixture of conformers): 12.7 (br s,1H), 8.77 (t, J=5.9 Hz, 1H), 8.27-8.21 (m, 1H), 7.78 (d, J=7.6 Hz, 1H),7.67-7.59 (m, 2H), 7.55-7.45 (m, 3H), 7.17 (d, J=8.4 Hz, 1H), 7.05 (t,J=7.6 Hz, 1H), 4.80-4.60 (m, 1H), 4.59 (d, J=5.9 Hz, 2H), 3.92 (s, 3H),2.72-2.61 (m, 0.5H), 2.40-2.28 (m, 0.5H), 2.25-2.14 (m, 1H), 2.14-1.92(m, 4H), 1.89-1.78 (m, 1H), 1.78-1.65 (m, 1H), 1.65-1.49 (m, 1H)

Example 31:N-[[4-[4-amino-1-(3-oxocyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

A solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (36 μL, 0.24 mmol) inMeCN (0.5 mL) was added to a solution ofN-[[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide(75 mg, 0.20 mmol) in MeCN (1.5 mL). The reaction mixture was stirredfor 30 min and then cyclohex-2-enone (18 μL, 0.19 mmol) was added. Themixture was then stirred for 72 h, quenched with water and diluted withEtOAc. The aqueous layer extracted with EtOAc. The combined organiclayer was dried over sodium sulfate and evaporated to dryness. Furtherpurification by flash column chromatography on silica gel affordedN-[[4-[4-amino-1-(3-oxocyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(30 mg, 0.06 mmol, 32% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.34 min, m/z 471.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.04 min, m/z 471.0 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.78 (t, J=6.2 Hz, 1H), 8.26 (s, 1H), 7.78(dd, J=7.6, 1.8 Hz, 1H, 7.65-7.63 (m, 2H), 7.52-7.49 (m, 3H), 7.17 (d,J=7.8 Hz, 1H), 7.04 (td, J=11.2, 1.0 Hz, 1H), 5.24-5.17 (m, 1H), 4.59(d, J=6.2 Hz, 2H), 3.92 (s, 3H), 3.08-2.99 (m, 1H), 2.71-2.66 (m, 1H),2.53-2.44 (m, 1H), 2.36-2.29 (m, 1H), 2.26-2.20 (m, 1H), 2.15-2.11 (m,1H), 2.03-1.95 (m, 1H), 1.83-1.72 (m, 1H).

Example 32: ethyl4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanecarboxylate

Ethyl 4-methylsulfonyloxycyclohexanecarboxylate

Following general procedure L, ethyl 4-hydroxycyclohexanecarboxylate(1.0 mL, 6.20 mmol) afforded crude ethyl4-methylsulfonyloxycyclohexanecarboxylate (1.55 g, 6.20 mmol, assumedquantitative) as a colourless oil.

¹H NMR (400 MHz, CDCl₃, δ) (1:1 mixture of conformers): 4.97-4.90 (m,0.5H), 4.71-4.61 (m, 0.5H), 4.17 (q, J=7.2 Hz, 1H), 4.15 (q, J=7.2 Hz,1H), 3.04 (s, 1.5H), 3.03 (s, 1.5H), 2.45-2.28 (m, 1H), 2.26-2.17 (m,1H), 2.13-2.02 (m, 2H), 2.02-1.89 (m, 1H), 1.87-1.54 (m, 4H), 1.28 (t,J=7.1 Hz, 1.5H), 1.27 (q, J=7.1 Hz, 1.5H)

Ethyl4-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanecarboxylate

Following general procedure M,3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.40 g, 5.36 mmol) and ethyl4-methylsulfonyloxycyclohexanecarboxylate (1.61 g, 6.44 mmol) gave ethyl4-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanecarboxylate(0.77 g, 1.49 mmol, 28% yield) as a yellow solid.

LC-MS (ES⁺, Method 1): 2.71 min, m/z 415.9 [M+H]⁺

Ethyl4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanecarboxylate

Following general procedure C, ethyl4-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanecarboxylate(544 mg, 1.91 mmol) and[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid (660 mg, 1.59mmol) gave ethyl4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanecarboxylate(762 mg, 1.37 mmol, 86% yield) as an off-white solid.

LC-MS (ES⁺, Method 1): 3.41 min, m/z 529.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.63 min, m/z 529.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ) (1:1 mixture of conformers): 8.77 (t, J=6.1Hz, 1H), 8.28-8.22 (m, 1H), 7.83-7.74 (m, 1H), 7.67-7.59 (m, 2H),7.55-7.44 (m, 3H), 7.17 (d, J=8.3 Hz, 1H), 7.05 (t, J=7.4 Hz, 1H),4.82-4.62 (m, 1H), 4.59 (d, J=6.0 Hz, 2H), 4.14 (q, J=7.1 Hz, 1H), 4.09(q, J=7.1 Hz, 1H), 3.92 (s, 3H), 2.76-2.68 (m, 0.5H), 2.47-2.37 (m,0.5H), 2.25-2.15 (m, 1H), 2.15-1.93 (m, 4H), 1.90-1.80 (m, 1H),1.80-1.68 (m, 1H), 1.67-1.53 (m, 1H), 1.22 (t, J=7.1 Hz, 1.5H), 1.21 (t,J=7.1 Hz, 1.5H)

Example 33:N-[[4-[4-amino-1-[4-(dimethylcarbamoyl)cyclohexyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

N-[[4-[4-Amino-1-[4-(dimethylcarbamoyl)cyclohexyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure F, 2 M dimethylamine in THF (0.14 mL, 0.28mmol) and4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanecarboxylicacid (50 mg, 0.10 mmol) gave after purification by flash columnchromatography on silica gel (DCM/MeOH 100:0 to 90:10) affordedN-[[4-[4-amino-1-[4-(dimethylcarbamoyl)cyclohexyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(17 mg, 0.03 mmol, 32% yield, isomer 1) as a white solid andN-[[4-[4-amino-1-[4-(dimethylcarbamoyl)cyclohexyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(20 mg, 0.04 mmol, 37% yield, isomer 2) as a white solid.

UPLC-MS (ES⁺, Long acidic, isomer 1): 3.09 min, m/z 528.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ, isomer 1): 8.77 (t, J=6.0 Hz, 1H), 8.24 (s,1H), 7.78 (dd, J=7.6, 1.8 Hz, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.55-7.46 (m,3H), 7.17 (d, J=8.2 Hz, 1H), 7.08-7.02 (m, 1H), 4.86-4.76 (m, 1H), 4.60(d, J=6.0 Hz, 2H), 3.92 (s, 3H), 3.03 (s, 3H), 2.90 (quint, J=5.2 Hz,1H), 2.82 (s, 3H), 2.43-2.31 (m, 2H), 2.06-1.93 (m, 2H), 1.88-1.77 (m,2H), 1.72-1.61 (m, 2H)

UPLC-MS (ES⁺, Long acidic, isomer 2): 3.04 min, m/z 528.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ, isomer 2): 8.77 (t, J=6.1 Hz, 1H), 8.25 (s,1H), 7.78 (dd, J=7.6, 1.8 Hz, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.56-7.46 (m,3H), 7.17 (d, J=8.3 Hz, 1H), 7.10-7.03 (m, 1H), 4.75-4.63 (m, 1H), 4.60(d, J=6.1 Hz, 2H), 3.92 (s, 3H), 3.06 (s, 3H), 2.83 (s, 3H), 2.80-2.69(m, 1H), 2.20-2.05 (m, 2H), 2.03-1.92 (m, 2H), 1.91-1.80 (m, 2H),1.68-1.52 (m, 2H).

Example 34:N-[[4-(4-amino-1-tetrahydropyran-3-yl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

Tetrahydropyran-3-yl methanesulfonate

To a solution of 3-hydroxytetrahydropyran (550 mg, 5.39 mmol) in DCM (30mL), cooled at 0° C. under nitrogen atmosphere, were added successivelytriethylamine (0.83 mL, 5.92 mmol) and methanesulfonyl chloride (0.46mL, 5.92 mmol). The reaction mixture was stirred at 0° C. for 1 h, thenquenched with water (15 mL) and extracted with DCM (3×15 mL). Theorganic phase was separated, filtered over hydrophobic fit andconcentrated under reduced pressure to afford tetrahydropyran-3-ylmethanesulfonate (967 mg, 4.29 mmol, 80% yield) as a clear pale yellowoil.

¹H NMR (400 MHz, CDCl₃, δ): 4.73 (m, 1H), 3.88-3.84 (m, 1H), 3.72-3.62(m, 3H), 3.07 (s, 3H), 2.12-2.04 (m, 1H), 2.00-1.88 (m, 2H), 1.69-1.60(m, 1H).

3-Iodo-1-tetrahydropyran-3-yl-pyrazolo[3,4-d]pyrimidin-4-amine

To a stirred solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (700mg, 2.68 mmol) and tetrahydropyran-3-yl methanesulfonate (967 mg, 5.36mmol) in DMF (65 mL) was added cesium carbonate (2.9 g, 6.70 mmol). Thereaction mixture was stirred for 16 h at 80° C. Once the reaction hasproceeded, the reaction mixture was concentrated under reduced pressure.EtOAc (200 mL) was added to the red-orange residue. The mixture wassonicated for 15 minutes, filtered over Buchner. The solid was washedwith EtOAc (3×50 mL). The filtrate was then washed with water (2×100mL), brine (2×100 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give an orange solid. Further purification byflash column chromatography on silica gel (DCM/EtOAc 100:0 to 0:100)afforded, 3-iodo-1-tetrahydropyran-3-yl-pyrazolo[3,4-d]pyrimidin-4-amine(536 mg, 0.93 mmol, 35% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.18 min, m/z 345.9 [M+H]⁺

N-[[4-(4-Amino-1-tetrahydropyran-3-yl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

Following general procedure D,3-iodo-1-tetrahydropyran-3-yl-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg,0.43 mmol) and [4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid(149 mg, 0.52 mmol) afforded, after further purification by flash columnchromatography (DCM/MeOH 100:0 to 95:5),N-[[4-(4-amino-1-tetrahydropyran-3-yl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide(30 mg, 0.06 mmol, 13% yield) as a red-orange solid.

UPLC-MS (ES⁺, Short acidic): 1.38 min, m/z 459.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.14 min, m/z 459.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 8.26 (s, 1H), 7.77(dd, J=7.7, 1.8 Hz, 1H), 7.64 (d, J=8.2 Hz, 2H), 7.52-7.47 (m, 3H), 7.17(d, J=7.7 Hz, 1H), 7.05 (td, J=7.7, 1.0 Hz, 1H), 4.77 (m, 1H), 4.59 (d,J=6.1 Hz, 2H), 3.98-3.88 (m, 5H), 3.72 (t, J=10.6 Hz, 1H), 3.42 (td,J=6.6, 2.8 Hz, 1H), 2.34-2.22 (m, 1H), 2.13-2.11 (m, 1H), 1.85-1.71 (m,2H).

Example 35:[(1R,4R)-4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclopent-2-en-1-yl]acetate

[(1R,4R)-4-[4-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclopent-2-en-1-yl]acetate

Following general procedure G,N-[[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide(150 mg, 0.40 mmol) and (1S,4R)-cis-4-acetoxy-2-cyclopenten-1-ol (97 mg,0.68 mmol) afforded[(1R,4R)-4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclopent-2-en-1-yl]acetate (98 mg, 0.20 mmol, 49% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.44 min, m/z 499.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.23 min, m/z 499.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 8.30 (s, 1H), 7.77(dd, J=7.7 Hz, 1.8, 1H), 7.65-7.60 (m, 2H), 7.55-7.46 (m, 3H), 7.17 (d,J=7.7 Hz, 1H), 7.05 (dt, J=7.7, 1.0 Hz, 1H), 6.25-6.17 (m, 2H),6.14-6.08 (m, 1H), 5.95-5.89 (m, 1H), 4.59 (d, J=6.1 Hz, 2H), 3.92 (s,3H), 2.63-2.55 (m, 1H), 2.43-2.31 (m, 1H), 2.05 (s, 3H).

Example 36:N-[[4-[4-amino-1-[(1R,4R)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

N-[[4-[4-Amino-1-[(1R,4R)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure H,[(1R,4R)-4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclopent-2-en-1-yl]acetate (211 mg, 0.25 mmol) affordedN-[[4-[4-amino-1-[(1R,4R)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(47 mg, 0.10 mmol, 41% yield) as a white solid after purification bymass-directed semi-preparative HPLC.

UPLC-MS (ES⁺, Short acidic): 1.22 min, m/z 457.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.70 min, m/z 457.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 8.21 (m, 1H), 7.77(dd, J=7.7, 1.8 Hz, 1H), 7.61 (d, J=8.2 Hz, 2H), 7.49 (m, 3H), 7.17 (d,J=7.7 Hz, 1H), 7.05 (dt, J=7.7, 0.9 Hz, 1H), 6.11 (m, 1H), 6.07 (m, 1H),5.95 (dd, J=7.4, 1.7 Hz, 1H), 5.01 (m, 2H), 4.58 (d, J=6.1 Hz, 2H), 3.91(s, 3H), 2.43 (m, 1H), 2.16 (m, 1H).

Example 37:N-[[4-[4-amino-1-(3-hydroxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

N-[[4-[4-Amino-1-(3-hydroxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Sodium borohydride (142 mg, 3.76 mmol) was added to a solution ofN-[[4-[4-amino-1-(3-oxocyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(177 mg, 0.38 mmol) in methanol (4 mL). The reaction mixture stirred atroom temperature for 2 h, and then quenched with a saturated ammoniumchloride solution and extracted with DCM. The combined organic layerswere dried over sodium sulfate and evaporated to dryness. The crudeproduct was purified by flash column chromatography on silica gel(DCM/MeOH 100:0 to 90:10) to affordN-[[4-[4-amino-1-(3-hydroxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(125 mg, 0.27 mmol, 71% yield) as a white solid.

LC-MS (ES⁺, Short acidic): 2.87 min, m/z 473.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.87 min, m/z 473.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ) (mixture of diastereoisomers): 8.78 (t,J=6.2 Hz, 1H), 8.24 (s, 1H), 7.78 (dd, J=7.7, 1.8, 1H), 7.66-7.63 (m,2H), 7.52-7.49 (m, 3H), 7.17 (d, J=8.0 Hz, 1H), 7.05 (td, J=11.1, 1.0Hz, 1H), 4.77 (d, J=4.8 Hz, 1H), 4.75-4.68 (m, 1H), 4.60 (d, J=6.2 Hz,2H), 3.92 (s, 3H), 3.65-3.57 (m, 1H), 2.13-2.11 (m, 1H), 1.95-1.77 (m,5H), 1.48-1.38 (m, 1H), 1.25-1.14 (m, 1H).

Example 38:N-[[4-(7-amino-3-cyclopentyl-pyrazolo[4,3-d]pyrimidin-1-yl)phenyl]methyl]-2-methoxy-benzamide

Methyl 2-cyano-2-cyclopentylidene-acetate

A solution of methyl cyanoacetate (10.5 mL, 118.88 mmol), cyclopentanone(10.5 mL, 118.88 mmol) and ammonium acetate (6.0 g, 77.27 mmol) andacetic acid (2.4 mL) in toluene (12 mL) was heated to reflux underDean-Stark conditions for 16 h. The reaction mixture was cooled to roomtemperature and the solvent removed in vacuo to afford the crude methyl2-cyano-2-cyclopentylidene-acetate (19.6 g, 118.65 mmol, assumedquantitative) as a dark brown thick oil.

¹H NMR (400 MHz, CDCl₃, δ): 3.81 (s, 3H), 2.98 (t, J=6.7 Hz, 2H), 2.80(t, J=6.7, 3H), 1.89-1.77 (m, 4H).

Methyl 2-cyano-2-cyclopentyl-acetate

Methyl 2-cyano-2-cyclopentylidene-acetate (19.6 g, 118.65 mmol) wasdissolved in MeOH (50 mL). The flask was evacuated and refilled withnitrogen before palladium (10 wt % on carbon powder, dry) (2.53 g, 2.37mmol) was added and the flask evacuated and purged with hydrogen. Thereaction mixture was stirred at room temperature under an atmosphere ofhydrogen for 72 h. The reaction mixture was filtered over celite and thefiltrate concentrated in vacuo. The crude product was purified by columnchromatography eluting with 0-50% EtOAc in heptane to afford methyl2-cyano-2-cyclopentyl-acetate (7.00 g, 41.86 mmol, 35% yield) as ayellow oil.

¹H NMR (400 MHz, CDCl₃, δ): 3.80 (s, 3H), 3.51 (d, J=6.7 Hz, 1H),2.53-2.43 (m, 1H), 2.93-1.82 (m, 2H), 1.78-1.67 (m, 2H), 1.65-1.55 (m,2H), 1.51-1.37 (m, 2H).

Methyl 2-[(E)-(4-bromophenyl)azo]-2-cyano-2-cyclopentyl-acetate

4-Bromoaniline (10.3 g, 60.0 mmol) was dissolved in hydrochloric acid (1M, 150 mL, 150.0 mmol) and dropwise added to an aqueous solution ofsodium nitrite (1 M, 60 mL, 60.0 mmol). The reaction mixture was thenstirred at room temperature for 1 h and then added dropwise to asolution of methyl 2-cyano-2-cyclopentyl-acetate (5.0 g, 30.0 mmol) inEtOH (42 mL) and water (556 mL) while maintaining a pH value of 7 byaddition of sodium acetate. The mixture was stirred in the thawing icebath for 16 h. The reaction was quenched with saturated ammoniumchloride and diluted with EtOAc. The phases were separated and theaqueous layer extracted with EtOAc. The organic layer was washed withbrine and dried over sodium sulfate. The solvent was removed underreduced pressure to afford the crude methyl2-[(E)-(4-bromophenyl)azo]-2-cyano-2-cyclopentyl-acetate (10.8 g, 30.8mmol, assumed quantitative yield) as a yellow oil.

UPLC-MS (ES⁺, Short acidic): 2.12 min, m/z 351.9 [M+H]⁺

(Z)—N-(4-Bromoanilino)cyclopentanecarboximidoyl cyanide

To a solution of methyl2-[(E)-(4-bromophenyl)azo]-2-cyano-2-cyclopentyl-acetate (10.8 g, 30.8mmol in THF (308 mL), cooled to 0° C., was added a 0.1 M solution ofsodium hydroxide (80.2 mL, 801.8 mmol). The reaction mixture was warmedto room temperature and stirred for another 16 h. Ammonium chloride wasadded and the mixture was diluted with EtOAc. The phases were separatedand the organic phase washed with citric acid, saturated sodiumbicarbonate solution and brine. The organic layer was dried over sodiumsulfate and concentrated in vacuo. Purification by flash columnchromatography on silica gel eluting with 0-20% EtOAc in heptaneafforded (Z)—N-(4-bromoanilino)cyclopentanecarboximidoyl cyanide (3.6 g,12.4 mmol, 40% yield) as an orange oil.

LC-MS (ES⁺, Method 1): 5.18 min, m/z 293.0 [M+H]⁺

4-Amino-2-(4-bromophenyl)-5-cyclopentyl-pyrazole-3-carbonitrile

Bromoacetonitrile (1.63 g, 13.63 mmol) and sodium tert-butoxide (1.19 g,12.39 mmol) were added to a solution of(Z)—N-(4-bromoanilino)cyclopentanecarboximidoyl cyanide (3.62 g, 12.39mmol) in tert-butanol (62 mL). The reaction was stirred at 25° C. for 1h, quenched by adding saturated ammonium chloride and diluted withEtOAc. The phases were separated and the aqueous layer was extractedwith EtOAc. The combined organic layers were washed with brine and driedover sodium sulfate. The solvent was removed under reduced pressure.Purification by flash column chromatography on silica gel eluting with0-25% EtOAc in heptane afforded4-amino-2-(4-bromophenyl)-5-cyclopentyl-pyrazole-3-carbonitrile (2.7 g,8.15 mmol, 66% yield) as a yellow oil.

UPLC-MS (ES⁺, Short acidic): 2.12 min, m/z 332.8 [M+H]⁺

1-(4-Bromophenyl)-3-cyclopentyl-pyrazolo[4,3-d]pyrimidin-7-amine

Formamidine acetate (6.29 g, 60.39 mmol) was added to a solution of4-amino-2-(4-bromophenyl)-5-cyclopentyl-pyrazole-3-carbonitrile (2.5 g,7.55 mmol) was dissolved in EtOH (75.5 mL). The reaction mixture washeated to 80° C. for 3 h and concentrated under reduced pressure. Thecrude product was purified by flash column chromatography on silica geleluting with 0-100% EtOAc in heptane to afford1-(4-bromophenyl)-3-cyclopentyl-pyrazolo[4,3-d]pyrimidin-7-amine (1.49g, 4.16 mmol, 55% yield) as a beige solid.

UPLC-MS (ES⁺, Short acidic): 1.66 min, m/z 359.8 [M+H]⁺

2-(Chloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a stirred solution of2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.0 mL, 53.75mmol) and chloroiodomethane (4.3 mL, 59.12 mmol) in anhydrous THF (100mL), cooled to −78° C., was added cold n-butyllithium solution (23.94mL, 59.12 mmol) dropwise. After stirring for 30 min at this temperature,chlorotrimethylsilane (8.2 mL, 64.50 mmol) was added dropwise. Afterstirring for 10 min, the reaction mixture was allowed to return to roomtemperature and stirred for 24 h. Water (80 mL) was added and themixture extracted with Et₂O (2×80 mL). The organic extracts werecombined, washed with water (2×80 mL), dried over MgSO₄ and concentratedin vacuo. The crude product was purified by flash column chromatographyon silica gel (Heptane/EtOAc 99:1 to 95:5) to yield2-(chloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.35 g, 24.65mmol, 46% yield) as a colourless oil.

¹H NMR (400 MHz, DMSO-d₆, δ): 2.99 (s, 2H), 1.32 (s, 12H).

Potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide

A solution of freshly prepared potassium bis(trimethylsilyl)amide (4.92g, 24.65 mmol) in dry THF (50 mL) was added dropwise to a solution of2-(chloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.35 g, 24.65mmol) in dry THF (50 mL) cooled to −78° C. After stirring for 15 min at−78° C., the cooling bath was removed and the mixture was stirred for anadditional 2 h at room temperature. Anhydrous MeOH (2 mL, 49.29 mmol)was then added at 0° C. After stirring for an additional 1 h at 0° C.,2-methoxybenzoyl chloride (7.3 mL, 49.29 mmol) was added. The reactionwas warmed to room temperature and stirred for 24 h. The reactionmixture was concentrated under vacuum to remove THF then the resultingresidue was diluted in anhydrous MeOH (50 mL) and cooled to 0° C. beforethe addition of a saturated solution of potassium hydrogen fluoride(7.70 g, 98.59 mmol). The reaction mixture was warmed to roomtemperature and stirred for 30 min and then concentrated under vacuum.The residue was triturated with hot acetone (2×500 mL) and filtered. Thefiltrate was concentrated under vacuum until the appearance of the firstcrystals. Et₂O (1500 mL) was then added. The precipitate was collectedby filtration to give potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (1.48 g, 5.45 mmol,22% yield) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆, δ): 10.34 (s, 1H), 7.95 (dd, J=8.0, 1.8 Hz,1H), 7.74 (m, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.17 (m, 1H), 3.98 (s, 3H),2.46 (t, J=9.9 Hz, 2H).

N-[[4-(7-Amino-3-cyclopentyl-pyrazolo[4,3-d]pyrimidin-1-yl)phenyl]methyl]-2-methoxy-benzamide

Following general procedure K, potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (75.7 mg, 0.28mmol) and1-(4-bromophenyl)-3-cyclopentyl-pyrazolo[4,3-d]pyrimidin-7-amine (100.0mg, 0.28 mmol) affordedN-[[4-(7-amino-3-cyclopentyl-pyrazolo[4,3-d]pyrimidin-1-yl)phenyl]methyl]-2-methoxy-benzamide(72 mg, 0.16 mmol, 58% yield) after purification by flash columnchromatography on silica gel (EtOAc/MeOH 100:0 to 80:20).

UPLC-MS (ES⁺, Short acidic): 1.49 min, m/z 443.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.44 min, m/z 443.5 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.79 (t, J=6.2 Hz, 1H), 8.29 (s, 1H), 7.77(dd, J=7.7, 1.8 Hz, 1H), 7.52 (m, 5H), 7.17 (d, J=7.7 Hz, 1H), 7.05 (dt,J=7.7, 1.0 Hz, 1H), 6.46 (s, 2H), 4.60 (d, J=6.2 Hz, 2H), 3.92 (s, 3H),3.46 (quint, J=8.3 Hz, 1H), 2.03 (m, 4H), 1.80 (m, 2H), 1.69 (m, 2H).

Example 39:N-[[4-[4-amino-1-(4-methoxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

4-[tert-Butyl(dimethyl)silyl]oxycyclohexanol

Sodium borohydride (83 mg, 2.19 mmol) was added to a solution of4-(tert-butyldimethylsilyloxy)cyclohexanone (0.5 mL, 1.99 mmol) inmethanol (4 mL), cooled to 0° C. The reaction mixture was stirred atroom temperature for 30 min, and then carefully quenched with asaturated solution of aqueous NH₄Cl (10 mL). The aqueous layer wasextracted with DCM (3×10 mL) and the combined organic extracts werefiltered over a phase separator, concentrated under reduced pressure togive crude 4-[tert-butyl(dimethyl)silyl]oxycyclohexanol (assumedquantitative) which was used directly in the next step.

¹H NMR (400 MHz, CDCl₃, δ) (2:1 mixture of conformers): 3.82-3.72 (m,0.6H), 3.69-3.53 (m, 1.4H), 1.96-1.18 (m, 9H), 0.90-0.78 (m, 9H),0.04-0.03 (m, 6H)

tert-Butyl-(4-methoxycyclohexoxy)-dimethyl-silane

To a solution of 4-[tert-butyl(dimethyl)silyl]oxycyclohexanol (0.14 mL,1.99 mmol) in THF (2.0 mL), cooled at 0° C. under nitrogen atmosphere,was added sodium hydride (60% dispersed in mineral oil) (111 mg, 2.78mmol). After allowing the reaction mixture to stir at 0° C. for 30 min,iodomethane (0.17 mL, 2.78 mmol) was added. The reaction mixture wasstirred at room temperature overnight, then carefully quenched with asaturated solution of ammonium chloride (10 mL). The aqueous layer wasextracted with DCM (3×10 mL). The organic layers were combined, filteredover a hydrophobic frit and concentrated under reduced pressure toafford crude tert-butyl-(4-methoxycyclohexoxy)-dimethyl-silane (assumedquantitative) as a yellow oil.

¹H NMR (400 MHz, CDCl₃, δ): 3.80-3.55 (m, 1H), 3.29 (s, 3H), 3.20-3.01(m, 1H), 2.00-1.86 (m, 1H), 1.86-1.37 (m, 7H), 0.90-0.78 (m, 9H),0.04-0.02 (m, 6H)

3-Iodo-1-(4-methoxycyclohexyl)pyrazolo[3,4-d]pyrimidin-4-amine

To a solution of tert-butyl-(4-methoxycyclohexoxy)-dimethyl-silane (486mg, 1.99 mmol) in THF (2.0 mL), cooled at 0° C. under nitrogenatmosphere, was added 1.0 M tetrabutylammonium fluoride in THF (4.0 mL,4.00 mmol). The reaction mixture was allowed to stir at room temperatureovernight, then quenched with water (20 mL). The aqueous layer wasextracted with DCM (3×10 mL). The organic extracts were combined,filtered over a hydrophobic frit and concentrated under reduced pressureto provide 4-methoxycyclohexanol (229 mg, 1.76 mmol, 89% yield) as ayellow oil. The residue was dissolved in DCM (2.0 mL), cooled to 0° C.under nitrogen atmosphere, and then methanesulfonyl chloride (0.18 mL,2.39 mmol) and triethylamine (0.42 mL, 2.98 mmol) were addedsuccessively. The reaction mixture was stirred at 0° C. for 1 h, andthen quenched with water (20 mL). The aqueous layer was extracted withDCM (3×10 mL). The organic extracts were combined, filtered over ahydrophobic fit and concentrated under reduced pressure to provide(4-methoxycyclohexyl) methanesulfonate (320 mg, 1.55 mmol, 78% yield) asa yellow oil. Then pyrazolo[3,4-d]pyrimidin-4-amine (400 mg, 1.53 mmol)was added and suspended in DMF (3 mL) under a nitrogen atmosphere.Afterwards, cesium carbonate (750 mg, 2.30 mmol) was added and thereaction mixture was allowed to stir at 80° C. for 16 h. Afterwards, thereaction mixture was concentrated under reduced pressure. The residuewas then partitioned between a layer of ethyl acetate (15 mL) and water(15 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL).The combined organic layers were washed with a saturated solution ofbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. Further purification by flash column chromatography on silicagel eluting 0-3% MeOH in DCM afforded3-iodo-1-(4-methoxycyclohexyl)pyrazolo[3,4-d]pyrimidin-4-amine (174 mg,0.47 mmol, 30% yield as a mixture of diasteroisomers) as a yellow solid.

UPLC-MS (ES⁺, Short acidic, isomer 1): 1.25 min, m/z 374.1 [M+H]⁺

UPLC-MS (ES⁺, Short acidic, isomer 2): 1.29 min, m/z 374.1 [M+H]⁺

N-[[4-[4-Amino-1-(4-methoxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure C,3-iodo-1-(4-methoxycyclohexyl)pyrazolo[3,4-d]pyrimidin-4-amine (150 mg,0.40 mmol) and [4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid(138 mg, 0.48 mmol) gaveN-[[4-[4-amino-1-(4-methoxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(762 mg, 1.37 mmol, 86% yield as a mixture of diastereoisomers) as awhite solid.

UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z 487.3 [M+H]⁺ (Isomer 1), 1.45min, m/z 487.3 [M+H]⁺ (Isomer 2)

UPLC-MS (ES⁺, Long acidic): 3.26 min, m/z 487.3 [M+H]⁺ (Isomer 1), 3.34min, m/z 487.3 [M+H]⁺ (Isomer 2)

¹H NMR (400 MHz, DMSO-d₆, δ) (2:1 mixture of diastereoisomers): 8.77 (t,J=6.0 Hz, 1H), 8.24 (s, 1H), 7.80-7.75 (m, 1H), 7.68-7.60 (m, 2H),7.55-7.45 (m, 3H), 7.17 (d, J=8.3 Hz, 1H), 7.09-7.02 (m, 1H), 4.80-4.63(m, 1H), 4.59 (d, J=6.0 Hz, 2H), 3.92 (s, 3H), 3.51-3.44 (m, 0.3H),3.31-3.21 (m, 3.7H), 2.30-1.89 (m, 5H), 1.74-1.55 (m, 1.3H), 1.45-1.30(m, 1.7H)

Example 40:N-[[4-(4-amino-1-cyclopent-3-en-1-yl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

1-Cyclopent-3-en-1-yl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine

Following general procedure G, a suspension of3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.38 mmol) and3-cyclopentene-1-ol (55 mg, 0.65 mmol) gave, after further purificationby flash column chromatography on silica gel,1-cyclopent-3-en-1-yl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (70 mg,0.11 mmol, 28% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.30 min, m/z 328.1 [M+H]⁺

N-[[4-(4-Amino-1-cyclopent-3-en-1-yl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

Following general procedure D,1-cyclopent-3-en-1-yl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (70 mg,0.21 mmol) and [4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid(91 mg, 0.32 mmol) afforded, after further purification by flash columnchromatography on silica gel,N-[[4-(4-amino-1-cyclopent-3-en-1-yl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide(25 mg, 0.05 mmol, 24% yield).

UPLC-MS (ES⁺, Short acidic): 1.47 min, m/z 441.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.38 min, m/z 441.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.76 (t, J=6.1 Hz, 1H), 8.25 (s, 1H), 7.76(dd, J=7.6, 1.7 Hz, 1H), 7.66-7.61 (m, 2H), 7.53-7.45 (m, 3H), 7.18-7.14(m, 1H), 7.07-7.01 (m, 1H), 5.81 (s, 2H), 5.63-5.54 (m, 1H), 4.58 (d,J=6.1 Hz, 2H), 3.91 (s, 3H), 2.94-2.74 (m, 4H).

Example 41: ethyl3-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanecarboxylate

Ethyl3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanecarboxylate

Following general procedure G,3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.92 mmol) and ethyl3-hydroxycyclohexanecarboxylate (0.5 mL, 3.26 mmol) afforded, afterfurther purification by flash column chromatography (DCM/EtOAc 100:0 to0:100), ethyl3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanecarboxylate(302 mg, 0.37 mmol, 19% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.50 min and 1.55 min, m/z 416.1 [M+H]⁺

Ethyl3-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanecarboxylate

Following general procedure D, ethyl3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanecarboxylate(100 mg, 0.29 mmol) and[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid (125 mg, 0.44mmol) gave, after further purification by flash column chromatography(DCM/MeOH 100:0 to 95:5), ethyl3-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanecarboxylate(21 mg, 0.03 mmol, 5% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.61 min and 1.63 min, m/z 529.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ) (2:1 mixture of diastereoisomers): 8.77 (t,J=6.1 Hz, 1H), 8.25 (s, 1H), 7.77 (dd, J=7.7, 1.8 Hz, 1H), 7.65 (d,J=8.2 Hz, 2H), 7.52-7.47 (m, 3H), 7.17 (d, J=7.7 Hz, 1H), 7.05 (td,J=7.7, 1.0 Hz, 1H), 5.00 (m, 0.3H), 4.79 (m, 0.7H), 4.59 (d, J=6.1 Hz,2H), 4.14 (q, J=7.3 Hz, 0.7H), 4.06 (q, J=7.1 Hz, 1.3H), 3.92 (s, 3H),2.28-1.31 (m, 8H), 1.23 (t, J=7.3 Hz, 1H), 1.17 (t, J=7.1 Hz, 2H).

Example 42:N-[[4-[4-amino-1-[3-(dimethylcarbamoyl)cyclohexyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Ethyl3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanecarboxylate

Following general procedure G,3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.92 mmol) and ethyl3-hydroxycyclohexanecarboxylate (0.5 mL, 3.26 mmol) afforded, afterfurther purification by flash column chromatography on silica gel(DCM/EtOAc 100:0 to 0:100), ethyl3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanecarboxylate(302 mg, 0.37 mmol, 19% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.50 min and 1.55 min, m/z 416.1 [M+H]⁺

Ethyl3-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanecarboxylate

Following general procedure D, ethyl3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanecarboxylate(100 mg, 0.29 mmol) and[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid (125 mg, 0.44mmol) afforded, after further purification by flash columnchromatography on silica gel (DCM/MeOH 100:0 to 95:5), ethyl3-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanecarboxylate(156 mg, 0.27 mmol, 37% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.61 min and 1.63 min, m/z 529.3 [M+H]⁺

3-[4-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanecarboxylicacid

Ethyl3-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanecarboxylate(156 mg, 0.30 mmol) was dissolved in a mixture of THF/EtOH (2 mL, 1:1)followed by the addition of sodium hydroxide (70.8 mg, 1.77 mmol) inwater (0.9 mL). The resulting mixture was then left to stir at roomtemperature overnight. Once the reaction has reached completion, 1 M HClwas then added to neutralise the pH of the reaction mixture to pH 3. Thesolvents were then removed under reduced pressure to afford a yellowgum. The residue was then washed with water and extracted with EtOAc(3×20 mL), washed with brine (10 mL) and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure to afford3-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanecarboxylicacid (130 mg, 0.26 mmol, 88% yield, mixture of diastereoisomers) as ayellow-brown solid.

UPLC-MS (ES⁺, Short acidic): 1.35 min and 1.38 min, m/z 501.2 [M+H]⁺

N-[[4-[4-Amino-1-[3-(dimethylcarbamoyl)cyclohexyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure F,3-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanecarboxylicacid (100 mg, 0.20 mmol) and dimethylamine (0.01 mL, 0.26 mmol)afforded, after further purification by flash column chromatography onsilica gel (DCM/MeOH 100:0 to 90:10),N-[[4-[4-amino-1-[3-(dimethylcarbamoyl)cyclohexyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(17 mg, 0.03 mmol, 14% yield, mixture of diastereoisomers) as a creamsolid.

UPLC-MS (ES⁺, Short acidic): 1.34 and 1.39 min, m/z 528.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.08 and 3.24 min, m/z 528.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ) (2:1 mixture of diastereoisomers): 8.77 (t,J=6.0 Hz, 1H), 8.24 (s, 1H), 7.76 (dd, J=7.7, 1.7 Hz, 1H), 7.65 (d,J=8.2 Hz, 2H), 7.52-7.47 (m, 3H), 7.17 (d, J=8.4 Hz, 1H), 7.07-7.03 (m,1H), 5.32 (m, 0.3H), 4.84 (m, 0.7H), 4.59 (d, J=6.1 Hz, 2H), 3.92 (s,3H), 3.05 (s, 2.1H), 3.00 (s, 0.9H), 2.82 (s, 0.9H), 2.80 (s, 2.1H),2.22-1.24 (m, 8H).

Example 43:N-[[4-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide

5-Fluoro-2-methoxy-benzoyl chloride

A solution of 5-fluoro-2-methoxybenzoic acid (10.0 g, 58.8 mmol) in DCM(200 mL) was cooled to 0° C. and oxalyl chloride (5.5 mL, 64.7 mmol) wasadded dropwise. The reaction mixture was allowed to warm to roomtemperature, stirred overnight and concentrated under reduced pressure.Further purification product by flash column chromatography on silicagel (heptane/EtOAc 70:30 to 0:100) gave the title compound (3.4 g, 18.1mmol, 31%) as white solid.

LC-MS (ES⁺, Method 1): 3.81 min, m/z 189.1 [M+H]⁺

[4-[[(5-Fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic Acid

Following general procedure B, 5-fluoro-2-methoxy-benzoyl chloride (2.85g, 15.1 mmol) and [4-(aminomethyl)phenyl]boronic acid hydrochloride(2.83 g, 15.1 mmol), after further recrystallization in DCM, affordedthe title compound (2.60 g, 7.90 mmol, 52%) as an white solid.

UPLC-MS (ES⁺, Short acidic): 1.46 min, m/z 304.1 [M+H]⁺

N-[[4-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure C,3-bromo-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-4-amine (1.00 g, 3.70mmol) and [4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronicacid (1.46 g, 4.44 mmol), after further recrystallization in DCM,affordedN-[[4-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide(226 mg, 0.49 mmol, 13%) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.77 min, m/z 449.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.81 min, m/z 449.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.87 (t, J=6.1 Hz, 1H), 8.24 (s, 1H), 7.63(d, J=8.3 Hz, 2H), 7.56-7.48 (m, 3H), 7.38-7.32 (m, 1H), 7.20 (dd,J=9.2, 4.3 Hz, 1H), 4.60 (d, J=5.9 Hz, 2H), 3.91 (s, 3H), 1.76 (s, 9H).

Example 44:N-[[4-[4-amino-1-[(1S,4R)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

[(1R,4R)-4-Acetoxycyclopent-2-en-1-yl] 2,2-dimethylpropanoate

Following general procedure G, (1S,4R)-cis-4-acetoxy-2-cyclopenten-1-ol(500 mg, 3.52 mmol) and trimethylacetic acid (548 mg, 5.36 mmol)afforded [(1R,4R)-4-acetoxycyclopent-2-en-1-yl] 2,2-dimethylpropanoate(663 mg, 2.93 mmol, 83% yield) after purification by flash columnchromatography on silica gel (heptane/EtOAc 100:0 to 75:15).

¹H NMR (400 MHz, DMSO-d₆, δ): 6.13 (m, 2H), 5.82 (m, 2H), 2.23 (m, 2H),2.07 (s, 3H), 1.20 (s, 9H).

[(1R,4R)-4-Hydroxycyclopent-2-en-1-yl] 2,2-dimethylpropanoate

A mixture of [(1R,4R)-4-acetoxycyclopent-2-en-1-yl]2,2-dimethylpropanoate (125 mg, 0.36 mmol) and potassium carbonate (50mg, 0.36 mmol) in MeOH (3.6 mL) was stirred at room temperature for 90minutes. The reaction mixture was then diluted with chloroform andwashed with an aqueous solution of NH₄Cl then brine. The organic layerwas dried over Na₂SO₄ and concentrated under vacuum to give[(1R,4R)-4-hydroxycyclopent-2-en-1-yl] 2,2-dimethylpropanoate (101 mg,0.36 mmol, 99% yield).

¹H NMR (400 MHz, DMSO-d₆, δ): 6.14 (m, 1H), 6.04 (m, 1H), 5.82 (m, 1H),5.09 (m, 1H), 2.22 (m, 2H), 1.33 (m, 1H), 1.19 (s, 9H).

[(1R,4S)-4-[4-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclopent-2-en-1-yl]2,2-dimethylpropanoate

Following general procedure G,N-[[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide(217 mg, 0.58 mmol) and [(1R,4R)-4-hydroxycyclopent-2-en-1-yl]2,2-dimethylpropanoate (101 mg, 0.36 mmol) afforded[(1R,4S)-4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclopent-2-en-1-yl]2,2-dimethylpropanoate (42 mg, 0.07 mmol, 19% yield)

UPLC-MS (ES⁺, Short acidic): 1.65 min, m/z 541.3 [M+H]⁺

N-[[4-[4-Amino-1-[(1S,4R)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure I,[(1R,4S)-4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclopent-2-en-1-yl]2,2-dimethylpropanoate (42 mg, 0.07 mmol) affordedN-[[4-[4-amino-1-[(1S,4R)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(5 mg, 0.01 mmol, 15% yield) after purification by mass-directedsemi-preparative HPLC.

UPLC-MS (ES⁺, Short acidic): 1.25 min, m/z 457.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.83 min, m/z 457.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 8.26 (m, 2H), 7.77(dd, J=7.7, 1.8 Hz, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.48 (m, 3H), 7.17 (d,J=7.7 Hz, 1H), 7.05 (dt, J=7.7, 0.9 Hz, 1H), 6.08 (dt, J=5.6, 2.0 Hz,1H), 5.92 (dt, J=5.6, 3.3 Hz, 1H), 5.75 (m, 1H), 4.74 (m, 1H), 4.59 (d,J=6.1 Hz, 2H), 3.92 (s, 3H), 2.83 (m, 1H), 1.99 (m, 1H).

Example 45:N-[[4-[4-amino-1-[(2R,4R)-4-hydroxy-2-bicyclo[3.1.0]hexanyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

[(2S,4R)-2-Hydroxy-4-bicyclo[3.1.0]hexanyl] acetate

Over a cooling bath at 0° C., (1S,4R)-cis-4-acetoxy-2-cyclopenten-1-ol(488 mg, 3.43 mmol) was dissolved in dichloromethane (15 mL) and treatedwith 1 M diethylzinc solution in hexanes (3.78 mL, 3.78 mmol). After themixture was stirred at 0° C. for 15 min, diiodomethane (0.61 mL, 7.55mmol) and 1 M diethylzinc solution in hexanes (3.78 mL, 3.78 mmol) wereadded. Fifteen minutes later, an additional amount of diiodomethane(0.61 mL, 7.55 mmol) was added. The reaction mixture was allowed toreach room temperature, and after being stirred for 6 h, the content waspoured onto a cold aqueous solution of NH₄Cl (60 mL). The mixture wasextracted with CHCl₃ (5×20 mL). The combined organic extracts were dried(MgSO₄), filtered, and evaporated in vacuo. The residue was purified byflash column chromatography on silica gel (heptane/EtOAc 100:0 to 50:50)to give [(2S,4R)-2-hydroxy-4-bicyclo[3.1.0]hexanyl] acetate (353 mg,2.26 mmol, 66% yield) as a colourless oil.

¹H NMR (400 MHz, CDCl₃, δ): 5.19-5.12 (m, 1H), 4.51-4.41 (m, 1H), 2.32(dt, J=13.4, 7.8 Hz, 1H), 2.04 (s, 3H), 1.76-1.69 (m, 1H), 1.69-1.60 (m,2H), 1.16 (dt, J=13.4, 8.9 Hz, 1H), 0.96-0.90 (m, 1H), 0.59-0.51 (m,1H).

[(2R,4R)-2-[4-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]-4-bicyclo[3.1.0]hexanyl]acetate

Following general procedure G,N-[[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide(200 mg, 0.42 mmol) and [(2S,4R)-2-hydroxy-4-bicyclo[3.1.0]hexanyl]acetate (98 mg, 0.63 mmol) afforded[(2R,4R)-2-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]-4-bicyclo[3.1.0]hexanyl]acetate (26 mg, 0.04 mmol, 10% yield).

UPLC-MS (ES⁺, Short acidic): 1.47 min, m/z 513.3 [M+H]⁺

N-[[4-[4-Amino-1-[(2R,4R)-4-hydroxy-2-bicyclo[3.1.0]hexanyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure H,[(2R,4R)-2-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]-4-bicyclo[3.1.0]hexanyl]acetate (26 mg, 0.05 mmol) affordedN-[[4-[4-amino-1-[(2R,4R)-4-hydroxy-2-bicyclo[3.1.0]hexanyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(10 mg, 0.02 mmol, 39% yield) after purification by flash columnchromatography (EtOAc/MeOH 100:0 to 80:20).

UPLC-MS (ES⁺, Short acidic): 1.22 min, m/z 471.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.76 min, m/z 471.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.78 (t, J=6.2 Hz, 1H), 8.24 (s, 1H), 7.78(dd, J=7.6, 1.8 Hz, 1H), 7.65 (d, J=8.3 Hz, 2H), 7.55-7.45 (m, 3H), 7.17(d, J=8.3 Hz, 1H), 7.05 (dt, J=7.6, 0.9 Hz, 1H), 5.25 (d, J=7.3 Hz, 1H),5.04-4.94 (m, 1H), 4.64-4.55 (m, 3H), 3.92 (s, 3H), 2.09-1.98 (m, 1H),1.69-1.58 (m, 2H), 1.46-1.38 (m, 1H), 0.75-0.69 (m, 1H), 0.57-0.49 (m,1H).

Example 46:[4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl]4-methyl benzoate

(4-Hydroxycyclohexyl) 4-methylbenzoate

To a solution of 1,4-cyclohexanediol (1.00 g, 8.61 mmol) in THF (40 mL),cooled at 0° C. under nitrogen atmosphere, was added triethylamine (1.2mL, 8.61 mmol) and p-toluoyl chloride (1.1 mL, 8.61 mmol). The reactionmixture was heated to 70° C. and stirred overnight. Once cooled, themixture was quenched with a saturated solution of NaHCO₃ (15 mL) andextracted with DCM (3×20 mL). The combined organic extracts werefiltered over hydrophobic fit and concentrated under reduced pressure.Further purification by flash column chromatography on silica geleluting 0-40% ethyl acetate in heptane afforded (4-hydroxycyclohexyl)4-methylbenzoate (0.49 g, 2.09 mmol, 24% yield as a mixture ofdiasteroisomers) as a white solid.

¹H NMR (400 MHz, CDCl₃, δ) (3:2 as a mixture of diasteroisomers):8.00-7.90 (m, 2H), 7.31-7.22 (m, 2H), 5.20-5.11 (m, 0.4H), 5.07-4.98 (m,0.6H), 3.90-3.77 (m, 1H), 2.46-2.41 (m, 3H), 2.20-1.43 (m, 9H)

(4-Methylsulfonyloxycyclohexyl) 4-methylbenzoate

Following general procedure L, (4-hydroxycyclohexyl) 4-methylbenzoate(490 mg, 2.09 mmol) afforded crude (4-methylsulfonyloxycyclohexyl)4-methylbenzoate (653 mg, 2.09 mmol, assumed quantitative) as acolourless oil.

¹H NMR (400 MHz, CDCl₃, δ) (3:2 as a mixture of diasteroisomers):8.00-7.89 (m, 2H), 7.31-7.22 (m, 2H), 5.18-5.09 (m, 1H), 4.96-4.78 (m,1H), 3.07 (s, 1H), 3.07 (s, 2H), 2.46-2.42 (m, 3H), 2.23-1.72 (m, 8H)

[4-(4-Amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl]4-methylbenzoate

Following general procedure M,3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (550 mg, 2.11 mmol) and(4-methylsulfonyloxycyclohexyl) 4-methylbenzoate (658 mg, 2.11 mmol)gave [4-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl]4-methylbenzoate (549 mg, 1.15 mmol, 55% yield as a mixture ofdiasteroisomers) as a yellow solid.

UPLC-MS (ES⁺, Short acidic, Isomer 1): 1.75 min, m/z 478.1 [M+H]⁺

UPLC-MS (ES⁺, Short acidic, Isomer 2): 1.82 min, m/z 478.1 [M+H]⁺

[4-[4-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl]4-methylbenzoate

Following general procedure C,[4-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl]4-methylbenzoate (500 mg, 1.05 mmol) and4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid (358 mg, 1.26mmol) gave[4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl]4-methylbenzoate (350 mg, 0.59 mmol, 57% yield as a mixture ofdiasteroisomers) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.77 min and 1.83 min, m/z 591.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 4.17 min and 4.34 min, m/z 591.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ) (3:2 mixture of diasteroisomers): 8.78 (t,J=6.1 Hz, 1H), 8.27 (s, 0.6H), 8.27 (s, 0.4H), 7.96 (d, J=8.2 Hz, 1.3H),7.90-7.86 (m, 0.7H), 7.78 (dt, J=7.6, 2.0 Hz, 1H), 7.66 (d, J=8.2 Hz,2H), 7.55-7.46 (m, 3H), 7.40-7.32 (m, 2H), 7.17 (d, J=8.0 Hz, 1H),7.09-7.02 (m, 1H), 5.25-5.19 (m, 0.6H), 5.05-4.93 (m, 0.4H), 4.91-4.76(m, 1H), 4.60 (d, J=6.1 Hz, 2H), 3.93-3.91 (m, 3H), 2.48-2.35 (m, 4H),2.27-1.69 (m, 7H).

Example 47:N-[[4-[4-amino-1-[(1R,4S)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

N-[[4-[4-Amino-1-[(1R,4S)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure I,[(1S,4R)-4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclopent-2-en-1-yl]2,2-dimethylpropanoate (169 mg, 0.31 mmol) affordedN-[[4-[4-amino-1-[(1R,4S)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(13 mg, 0.03 mmol, 9% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.27 min, m/z 457.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.83 min, m/z 457.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.78 (t, J=6.1 Hz, 1H), 8.25 (s, 1H), 7.77(dd, J=7.7, 1.8 Hz, 1H), 7.63 (m, 2H), 7.49 (m, 3H), 7.16 (dd, J=8.5,0.5 Hz, 1H), 7.05 (dt, J=7.5, 0.9 Hz, 1H), 6.08 (dt, J=5.5, 2.0 Hz, 1H),5.91 (dt, J=5.5, 3.3 Hz, 1H), 5.74 (m, 1H), 5.32 (m, 1H), 4.74 (m, 1H),4.59 (d, J=6.1 Hz, 2H), 3.91 (s, 3H), 2.83 (m, 1H), 1.98 (m, 1H).

Example 48:[(1S,4R)-4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclopent-2-en-1-yl]2,2-dimethylpropanoate

[(1S,4R)-4-[4-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclopent-2-en-1-yl]2,2-dimethylpropanoate

Following general procedure G,N-[[4-[4-amino-1-[(1R,4R)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(250 mg, 0.46 mmol) and trimethylacetic acid (72 mg, 0.70 mmol) afforded[(1S,4R)-4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclopent-2-en-1-yl]2,2-dimethylpropanoate (169 mg, 0.30 mmol, 66% yield).

UPLC-MS (ES⁺, Short acidic): 1.66 min, m/z 541.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.93 min, m/z 541.5 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 8.27 (s, 1H), 7.77(dd, J=7.6, 1.8 Hz, 1H), 7.63 (d, J=8.1 Hz, 2H), 7.51-7.47 (m, 3H), 7.17(d, J=8.1 Hz, 1H), 7.05 (dt, J=7.6, 0.9 Hz, 1H), 6.19-6.17 (m, 1H),6.12-6.11 (m, 1H), 5.91-5.87 (m, 1H), 5.66-5.63 (m, 1H), 4.58 (d, J=6.1Hz, 2H), 3.91 (s, 3H), 3.00-2.96 (m, 1H), 2.08-2.03 (m, 1H), 1.14 (s,9H).

Example 49:N-[[4-(4-amino-1-cyclohex-2-en-1-yl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

1-Cyclohex-2-en-1-yl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine

Following general procedure G, a suspension of3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.00 g, 3.83 mmol) and2-cyclohexenol (639 mg, 6.51 mmol) afforded1-cyclohex-2-en-1-yl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (768 mg,1.58 mmol, 41% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.44 min, m/z 342.1 [M+H]⁺

N-[[4-(4-Amino-1-cyclohex-2-en-1-yl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

Following general procedure D,1-cyclohex-2-en-1-yl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg,0.29 mmol) and [4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid(125 mg, 0.44 mmol) afforded, after further purification by flash columnchromatography on silica gel,N-[[4-(4-amino-1-cyclohex-2-en-1-yl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide(39 mg, 0.08 mmol, 27% yield) as a pale cream solid.

UPLC-MS (ES⁺, Short acidic): 1.54 min, m/z 455.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.58 min, m/z 455.5 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.76 (t, J=6.1 Hz, 1H), 8.24 (s, 1H), 7.77(dd, J=7.6, 1.8 Hz, 1H), 7.65-7.60 (m, 2H), 7.53-7.45 (m, 3H), 7.18-7.14(m, 1H), 7.04 (td, J=7.6, 0.7 Hz, 1H), 6.00-5.91 (m, 1H), 5.73-5.65 (m,1H), 5.49-5.40 (m, 1H), 4.58 (d, J=6.1 Hz, 2H), 3.91 (s, 3H), 2.21-1.99(m, 4H), 1.97-1.88 (m, 1H), 1.80-1.60 (m, 1H).

Example 50:N-[[4-[4-amino-1-[(1S,4S)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

[(1S,4S)-4-[4-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclopent-2-en-1-yl]2,2-dimethylpropanoate

Following general procedure G,N-[[4-[4-amino-1-[(1S,4R)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(75 mg, 0.16 mmol) and trimethylacetic acid (26 mg, 0.25 mmol) afforded[(1S,4S)-4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclopent-2-en-1-yl]2,2-dimethylpropanoate (61 mg, 0.11 mmol, 69% yield) as a colourlessoily solid.

UPLC-MS (ES⁺, Short acidic): 1.72 min, m/z 541.4 [M+H]⁺

N-[[4-[4-Amino-1-[(1S,4S)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure I,[(1S,4S)-4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclopent-2-en-1-yl]2,2-dimethylpropanoate (61 mg, 0.11 mmol) affordedN-[[4-[4-amino-1-[(1S,4S)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(9 mg, 0.02 mmol, 16% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.21 min, m/z 457.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.70 min, m/z 457.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 8.26 (s, 1H), 7.77(dd, J=7.7, 1.8 Hz, 1H), 7.61 (d, J=8.2 Hz, 2H), 7.47 (m, 3H), 7.16 (d,J=7.7 Hz, 1H), 7.05 (dt, J=7.5, 1.0 Hz, 1H), 6.11 (m, 1H), 6.08 (m, 1H),5.95 (dd, J=7.5, 2.0 Hz, 1H), 5.01 (m, 2H), 4.58 (d, J=6.1 Hz, 2H), 3.91(s, 3H), 2.45 (m, 1H), 2.14 (m, 1H).

Example 51:N-[[4-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

N-[[4-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

Following general procedure C,3-bromo-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-4-amine (3.03 g, 11.22mmol) and [4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid (3.20g, 11.22 mmol) affordedN-[[4-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide(2.50 g, 5.86 mmol, 52% yield).

UPLC-MS (ES⁺, Short acidic): 1.63 min, m/z 431.5 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.52 min, m/z 431.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 8.24 (s, 1H), 7.78(dd, J=6.0, 1.7 Hz, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.56-7.44 (m, 3H), 7.17(d, J=8.2 Hz, 1H), 7.09-7.01 (m, 1H), 6.98-6.16 (br s, 2H), 4.59 (d,J=6.1 Hz, 2H), 3.92 (s, 3H), 1.75 (s, 9H).

Example 52:N-[[4-[4-amino-1-(3-bicyclo[3.1.0]hexanyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

1-(3-Bicyclo[3.1.0]hexanyl)-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine

Following general procedure G, a solution of3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (300 mg, 0.90 mmol) andcis-bicyclo[3.1.0]hexan-3-ol (132 mg, 1.34 mmol) gave, afterpurification by flash column chromatography on silica gel,1-(3-bicyclo[3.1.0]hexanyl)-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (120mg, 0.25 mmol, 27% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.58 min, m/z 342.1 [M+H]⁺

N-[[4-[4-Amino-1-(3-bicyclo[3.1.0]hexanyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure D,1-(3-bicyclo[3.1.0]hexanyl)-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (120mg, 0.35 mmol) and [4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronicacid (150 mg, 0.53 mmol) afforded, after further purification by flashcolumn chromatography on silica gel,N-[[4-[4-amino-1-(3-bicyclo[3.1.0]hexanyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(63 mg, 0.12 mmol, 35% yield) as a cream solid.

UPLC-MS (ES⁺, Short acidic): 1.59 min, m/z 455.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.64 min, m/z 455.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.0 Hz, 1H), 8.22 (s, 1H), 7.77(dd, J=7.7, 1.8 Hz, 1H), 7.66-7.61 (m, 2H), 7.53-7.45 (m, 3H), 7.18-7.14(m, 1H), 7.04 (td, J=7.7, 1.0 Hz, 1H), 4.99-4.88 (m, 1H), 4.58 (d, J=6.0Hz, 2H), 3.91 (s, 3H), 2.44-2.35 (m, 2H), 2.21-2.11 (m, 2H), 1.50-1.37(m, 2H), 0.53-0.36 (m, 2H).

Example 53:N-[[4-[4-Amino-1-[(1R,4R)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

N-[[4-(4-Amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure E,N-[[4-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide(2.69 g, 4.19 mmol) gaveN-[[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide(381 mg, 0.97 mmol, 23% yield).

UPLC-MS (ES+, Short acidic): 1.37 min, m/z 394.1 [M+2]⁺

[(1R,4R)-4-[4-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclopent-2-en-1-yl]acetate

Following general procedure G,N-[[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide(349 mg) afforded[(1R,4R)-4-[4-Amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclopent-2-en-1-yl]acetate (81 mg, 0.16 mmol, 18% yield) after purification by reversephase column chromatography.

UPLC-MS (ES+, Short acidic): 1.61 min, m/z 518.2 [M+2]⁺

N-[[4-[4-Amino-1-[(1R,4R)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure H,[(1R,4R)-4-[4-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclopent-2-en-1-yl]acetate (81 mg, 0.16 mmol) affordedN-[[4-[4-amino-1-[(1R,4R)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(26 mg, 0.05 mmol, 32% yield) as a white solid.

UPLC-MS (ES+, Short acidic): 1.41 min, m/z 474.2 [M]⁺

UPLC-MS (ES⁺, Long acidic): 3.14 min, m/z 476.2 [M+2]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.81 (t, J=6.0 Hz, 1H), 8.27-8.21 (m, 2H),8.10 (s, 1H), 7.51 (dd, J=9.2, 3.3 Hz, 1H), 7.41-7.37 (m, 2H), 7.36-7.30(m, 1H), 7.18 (dd, J=9.2, 4.2 Hz, 1H), 6.14 (dt, J=5.6, 2.1 Hz, 1H),6.05-5.99 (m, 1H), 5.95 (ddd, J=5.6, 2.1, 1.0 Hz, 1H), 5.09-5.01 (m,2H), 4.53 (d, J=6.0 Hz, 2H), 3.90 (s, 3H), 2.47-2.39 (m, 1H), 2.15 (ddd,J=13.7, 8.2, 3.1 Hz, 1H).

Example 54:N-[(4-{4-amino-1-[(1R,4R)-4-fluorocyclopent-2-en-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)methyl]-2-methoxybenzamide

N-[(4-{4-Amino-1-[(1R,4R)-4-fluorocyclopent-2-en-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)methyl]-2-methoxybenzamide

To a solution ofN-[[4-[4-amino-1-[(1R,4S)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(47 mg, 0.10 mmol) in anhydrous DCM (2 mL) at −78° C. under a nitrogenatmosphere, was added neat diethylaminosulfurtrifluoride (41 μL, 0.31mmol) over 10 minutes and the mixture was stirred at −78° C. for 105minutes. After this time reaction was quenched with the careful additionof a saturated aqueous Na₂CO₃ solution (5 mL). The organic layer waswashed with brine (10 mL), dried over Na₂SO₄ and concentrated undervacuum. The crude material was purified by flash column chromatographyon silica gel (Heptane/EtOAc 100:0 to 0:100) to giveN-[(4-{4-amino-1-[(1R,4R)-4-fluorocyclopent-2-en-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)methyl]-2-methoxybenzamide(24 mg, 0.05 mmol, 48% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.48 min, m/z 459.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.31 min, m/z 459.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.0 Hz, 1H), 8.27 (s, 1H), 7.77(dd, J=7.8, 1.8 Hz, 1H), 7.62 (d, J=8.2 Hz, 2H), 7.49 (m, 3H), 7.17 (d,J=7.8 Hz, 1H), 7.05 (dt, J=7.5, 0.9 Hz, 1H), 6.36 (m, 1H), 6.32 (m, 1H)6.16 (m, 1H), 6.05 (m, 1H), 4.58 (d, J=6.0 Hz, 2H), 3.92 (s, 3H), 2.52(m, 2H).

Example 55:N-[(4-{4-amino-1-[(1R,4R)-4-ethoxycyclopent-2-en-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)methyl]-2-methoxybenzamide

N-[(4-{4-Amino-1-[(1R,4R)-4-ethoxycyclopent-2-en-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)methyl]-2-methoxybenzamide

To a solution ofN-[[4-[4-amino-1-[(1R,4R)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(50 mg, 0.11 mmol) in toluene (2.7 mL) was added sodium hydride (60%dispersed in mineral oil) (5 mg, 0.12 mmol) at 0° C. and the mixturestirred at 0° C. for 1 h. After this time iodoethane (10 μL, 0.12 mmol)was added and the reaction mixture was stirred at 0° C. for another hourand then heated to reflux for 24 h. The mixture was cooled to roomtemperature, quenched with water and partitioned. The aqueous layer wasextracted with DCM, dried over Na₂SO₄ and concentrated under vacuum. Thecrude material was purified by mass-directed semi-preparative HPLC togiveN-[(4-{4-amino-1-[(1R,4R)-4-ethoxycyclopent-2-en-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)methyl]-2-methoxybenzamide(5 mg, 0.01 mmol, 8% yield).

UPLC-MS (ES⁺, Short acidic): 1.47 min, m/z 485.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.18 min, m/z 485.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 8.33 (s, 1H), 7.77(dd, J=7.6 Hz, 1.8, 1H), 7.61 (d, J=8.1 Hz, 2H), 7.50 (m, 3H), 7.17 (d,J=8.1 Hz, 1H), 7.05 (dt, J=7.6, 0.9 Hz, 1H), 6.33 (t, J=5.6 Hz, 1H),6.11 (m, 1H), 6.06 (m, 1H), 5.95 (dd, J=5.6, 2.1 Hz, 1H), 5.01 (br, 2H),4.59 (d, J=6.1 Hz, 2H), 3.92 (s, 3H), 3.52 (m, 2H), 2.43 (m, 1H), 2.17(m, 1H), 1.13 (t, J=7.1 Hz, 3H).

Example 56:N-[(4-{4-amino-1-[(1R)-2,3-dihydro-1H-inden-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)methyl]-2-methoxybenzamide

N-[(4-{4-amino-1-[(1R)-2,3-dihydro-1H-inden-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)methyl]-2-methoxybenzamide

Following general procedure G,N-[[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide(75 mg, 0.20 mmol) and (1S)-indan-1-ol (46 mg, 0.34 mmol) affordedN-[(4-{4-amino-1-[(1R)-2,3-dihydro-1H-inden-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)methyl]-2-methoxybenzamide(20 mg, 0.04 mmol, 20% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.71 min, m/z 491.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.84 min, m/z 491.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.74 (t, J=6.0 Hz, 1H), 8.31 (s, 1H), 7.76(dd, J=7.7, 1.7 Hz, 1H), 7.58 (d, J=8.1 Hz, 2H), 7.48 (m, 3H), 7.35 (d,J=7.5 Hz, 1H), 7.25 (t, J=7.5 Hz, 1H), 7.12 (m, 2H), 7.04 (t, J=7.3 Hz,1H), 6.94 (d, J=7.3 Hz, 1H), 6.45 (t, J=7.5 Hz, 1H), 4.56 (d, J=6.0 Hz,2H), 3.90 (s, 3H), 3.22 (m, 1H), 3.03 (m, 1H), 2.64 (m, 2H).

Example 57:N-[[4-[4-amino-1-[(1R,4R)-4-(2-methoxyethoxy)cyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Example 58:N-[[4-[1-[(1R,4R)-4-hydroxycyclopent-2-en-1-yl]-4-(2-methoxyethylamino)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

N-[[4-[1-[(1R,4R)-4-hydroxycyclopent-2-en-1-yl]-4-(2-methoxyethylamino)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(Example 58) andN-[[4-[4-amino-1-[(1R,4R)-4-(2-methoxyethoxy)cyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(Example 57)

Example 57 and Example 58 were Prepared from the Same SyntheticProcedure and Separated

To a solution ofN-[[4-[4-amino-1-[(1R,4R)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(95 mg, 0.21 mmol) in DMF (5 mL) was added sodium hydride (60% dispersedin mineral oil) (9 mg, 0.23 mmol) at 0° C. and the mixture stirred at 0°C. for 1 h. After this time 1-bromo-2-methoxy-ethane (22 μL, 0.23 mmol)was added and the reaction warmed to room temperature and stirred for 72h. A further sodium hydride (60% dispersed in mineral oil) (9 mg, 0.23mmol) and 1-bromo-2-methoxy-ethane (22 μL, 0.23 mmol) were added. Thereaction stirred at room temperature for 1 h then heated to 40° C. andstirred for 48 h. The mixture was cooled to room temperature, quenchedwith water and partitioned. The aqueous layer was extracted with DCM,dried over Na₂SO₄ and concentrated under vacuum. The crude material waspurified after purification by mass-directed semi-preparative HPLC,followed by salt removal SCX SPE cartridge filtration to giveN-[[4-[1-[(1R,4R)-4-hydroxycyclopent-2-en-1-yl]-4-(2-methoxyethylamino)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(2 mg, 0.01 mmol, 2% yield) andN-[[4-[4-amino-1-[(1R,4R)-4-(2-methoxyethoxy)cyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(6 mg, 0.01 mmol, 5% yield).

N-[[4-[1-[(1R,4R)-4-hydroxycyclopent-2-en-1-yl]-4-(2-methoxyethylamino)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

UPLC-MS (ES⁺, Short acidic): 1.29 min, m/z 515.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.18 min, m/z 515.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 8.26 (s, 1H), 7.77(dd, J=7.7, 1.8 Hz, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.50 (m, 3H), 7.17 (d,J=7.7 Hz, 1H), 7.05 (dt, J=7.7, 1.0 Hz, 1H), 6.30-6.24 (m, 1H),6.11-6.00 (m, 2H), 4.92-4.86 (m, 1H), 4.58 (d, J=6.1 Hz, 2H), 3.91 (s,3H), 3.62-3.56 (m, 2H), 3.49-3.44 (m, 2H), 3.26 (s, 3H), 2.57.2.52 (m,2H), 2.46-2.38 (m, 1H 2.35-2.24 (m, 1H).

N-[[4-[4-amino-1-[(1R,4R)-4-(2-methoxyethoxy)cyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamideUPLC-MS (ES⁺, Short acidic): 1.43 min, m/z 515.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.23 min, m/z 515.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.79 (t, J=6.2 Hz, 1H), 8.34 (s, 1H), 7.77(dd, J=7.7, 1.8 Hz, 1H), 7.61 (d, J=8.2 Hz, 2H), 7.50 (m, 3H), 7.17 (d,J=7.7 Hz, 1H), 7.05 (dt, J=7.7, 1.0 Hz, 1H), 6.22 (t, J=5.4 Hz, 1H),6.11 (m, 1H), 6.08 (m, 1H), 5.96 (m, 1H), 5.01 (br s, 2H), 4.60 (d,J=6.2 Hz, 2H), 3.92 (s, 3H), 3.65 (quint, J=5.5 Hz, 2H), 3.49 (t, J=5.5Hz, 2H), 3.23 (s, 3H), 2.44 (m, 1H), 2.15 (m, 1H).

Example 59:N-[(4-{4-amino-1-[(1R,4R)-4-aminocyclopent-2-en-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)methyl]-2-methoxybenzamide

N-[[4-[4-Amino-1-[(1R,4R)-4-azidocyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

To a solution ofN-[[4-[4-amino-1-[(1R,4S)-4-hydroxycyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(562 mg, 1.23 mmol) in toluene (12 mL), cooled to 0° C., were addeddiphenyl phosphoryl azide (318 μL, 1.48 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (258 μL, 1.72 mmol). The reactionmixture was stirred at room temperature overnight, cooled to 0° C. and afurther diphenyl phosphoryl azide (318 μL, 1.48 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (258 μL, 1.72 mmol) were added. Thereaction mixture was stirred at room temperature for another 2 h,partitioned between EtOAc and water. The organic layer was washedsequentially with water, 1 M HCl and brine, dried over Na₂SO₄ andconcentrated under vacuum to giveN-[[4-[4-amino-1-[(1R,4R)-4-azidocyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(709 mg, 0.96 mmol, 78% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.57 min, m/z 482.2 [M+H]⁺

N-[[4-[4-Amino-1-[(1R,4R)-4-aminocyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

A solution ofN-[[4-[4-amino-1-[(1R,4R)-4-azidocyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(150 mg, 0.31 mmol) was dissolved in MeOH (5 mL) and treated withtin(II) chloride dihydrate (127 mg, 0.56 mmol). The reaction mixture wasstirred at room temperature overnight before being treated with 1 M aq.NaOH and partitioned. The aqueous layer was extracted with EtOAc (×2).The combined organic extracts were washed with 1 M aq. HCl then water.The pH of the combined aqueous layers was adjusted to 11 with a 5 M aq.NaOH solution and then extracted with EtOAc (×2). The combined organicextracts were dried over Na₂SO₄ and concentrated under vacuum. The crudematerial was purified by flash column chromatography on silica gel(DCM/MeOH 100:0 to 70:30) to giveN-[[4-[4-amino-1-[(1R,4R)-4-aminocyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(17 mg, 0.04 mmol, 11% yield).

UPLC-MS (ES⁺, Short acidic): 1.15 min, m/z 456.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.46 min, m/z 456.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 8.26 (s, 1H), 7.77(dd, J=7.7, 1.8 Hz, 1H), 7.61 (d, J=8.2 Hz, 2H), 7.51 (m, 3H), 7.17 (d,J=7.7 Hz, 1H), 7.05 (dt, J=7.7, 0.9 Hz, 1H), 6.13 (m, 1H), 6.09 (m, 1H),6.04 (m, 1H), 4.59 (d, J=6.1 Hz, 2H), 4.38 (m, 1H), 3.92 (s, 3H), 2.47(m, 1H), 2.20 (m, 1H), 1.91 (s, 2H).

Example 60:N-[[4-[1-[(1R,4R)-4-acetamidocyclopent-2-en-1-yl]-4-amino-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

N-[[4-[1-[(1R,4R)-4-acetamidocyclopent-2-en-1-yl]-4-amino-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

A solution ofN-[[4-[4-amino-1-[(1R,4R)-4-aminocyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(60 mg, 0.09 mmol) and N,N-diisopropylethylamine (18 μL, 0.10 mmol) inDCM (2 mL) was cooled to −78° C. Acetyl chloride (7 μL, 0.10 mmol) wasadded dropwise and the reaction mixture was stirred at −78° C. for 2 h,quenched with a saturated aqueous solution of NH₄Cl and partitioned. Theaqueous layer was extracted with DCM, dried over Na₂SO₄ and concentratedunder vacuum. The crude material was purified by flash columnchromatography on silica gel (EtOAc/7N NH₃ in MeOH 90:10 to 80:20) togiveN-[[4-[1-[(1R,4R)-4-acetamidocyclopent-2-en-1-yl]-4-amino-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(12 mg, 0.02 mmol, 24% yield)

UPLC-MS (ES⁺, Short acidic): 1.29 min, m/z 498.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.80 min, m/z 498.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.77 (t, J=6.1 Hz, 1H), 8.26 (s, 1H), 8.12(d, J=7.7 Hz, 1H), 7.77 (dd, J=7.7, 1.8 Hz, 1H), 7.62 (d, J=8.3 Hz, 2H),7.49 (m, 3H), 7.17 (d, J=8.3 Hz, 1H), 7.05 (dt, J=7.7 Hz, 1.0, 1H), 6.09(m, 1H), 6.04 (m, 1H), 6.00 (m, 1H), 5.14 (m, 1H), 4.59 (d, J=6.1 Hz,2H), 3.92 (s, 3H), 2.46 (m, 1H), 2.15 (m, 1H), 1.83 (s, 3H).

Example 61:N-[[4-[4-amino-1-[(1R,4R)-4-(triazol-1-yl)cyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

N-[[4-[4-amino-1-[(1R,4R)-4-(triazol-1-yl)cyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

2,5-Norbornadiene (0.1 mL, 0.97 mmol) was added to a mixture ofN-[[4-[4-amino-1-[(1R,4R)-4-azidocyclopent-2-en-1-yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(47 mg, 0.10 mmol) in 1,4-dioxane (5 mL). The reaction mixture washeated for 18 h at 110° C. The reaction mixture was cooled to roomtemperature and concentrated under vacuum. Further purification bymass-directed semi-preparative HPLC gaveN-[[4-[4-amino-1-[(1R,4R)-4-(1H-1,2,3-triazol-1-yl)cyclopent-2-en-1-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxybenzamide(5 mg, 0.01 mmol, 9% yield).

UPLC-MS (ES⁺, Short acidic): 1.38 min, m/z 508.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.96 min, m/z 508.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.78 (t, J=6.1 Hz, 1H), 8.40 (br, 2H),8.29 (s, 1H), 8.24 (d, J=1.0 Hz, 1H), 7.78 (m, 2H), 7.66 (d, J=8.3 Hz,2H), 7.50 (m, 3H), 7.17 (d, J=7.8 Hz, 1H), 7.05 (dt, J=7.8, 1.0 Hz, 1H),6.32 (m, 3H), 6.16 (m, 1H), 4.60 (d, J=6.1 Hz, 2H), 3.92 (s, 3H), 3.00(m, 2H).

Example 62:N-[[4-[4-amino-1-(3-methylcyclopentyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

N-[[4-[4-Amino-1-(3-methylcyclopentyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure G,N-[[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide(150 mg, 0.40 mmol) and 3-methylcyclopentanol (79 mg, 0.40 mmol)affordedN-[[4-[4-amino-1-(3-methylcyclopentyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(7 mg, 0.02 mmol, 4% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.71 min, m/z 457.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.91 min, m/z 457.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ) (mixture of diastereoisomers): 8.78 (t,J=6.1 Hz, 1H), 8.24 (s, 1H), 7.78 (dd, J=7.6, 1.8 Hz, 1H), 7.68-7.61 (m,2H), 7.54-7.46 (m, 3H), 7.17 (d, J=7.8 Hz, 1H), 7.05 (dt, J=7.5, 0.9 Hz,1H), 5.40-5.20 (m, 1H), 4.59 (d, J=6.1 Hz, 2H), 3.92 (s, 3H), 2.50-1.20(m, 7H), 1.14-0.99 (m, 3H).

Example 63:N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

3-[4-(Aminomethyl)-3-fluoro-phenyl]-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-4-amine

Following general procedure D, a mixture of3-bromo-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-4-amine (329 mg, 1.17mmol) and [4-(aminomethyl)-3-fluoro-phenyl]boronic acid (369 mg, 1.75mmol) gave, after further purification by flash column chromatography(DCM/7 N NH₃ in MeOH 90:10 to 80:20)3-[4-(aminomethyl)-3-fluoro-phenyl]-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-4-amine(251 mg, 0.77 mmol, 66% yield) as a beige solid.

UPLC-MS (ES+, Short acidic): 1.10 min, m/z 327.3 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure F,3-[4-(aminomethyl)-3-fluoro-phenyl]-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-4-amine(75 mg, 0.23 mmol) and 5-fluoro-2-methoxybenzoic acid (37 mg, 0.22 mmol)gave, after further purification by flash column chromatography(DCM/MeOH 100:0 to 90:10) and filtration over Si—CO₃ SPE cartridge,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide(36 mg, 0.07 mmol, 32% yield) as an off-white solid.

UPLC-MS (ES+, Short acidic): 1.80 min, m/z 479.3 [M+H]⁺

UPLC-MS (ES+, Long acidic): 4.04 min, m/z 479.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.85 (t, J=6.1 Hz, 1H), 8.24 (s, 1H),7.57-7.50 (m, 2H), 7.48 (dd, J=7.8, 1.6 Hz, 1H), 7.44 (dd, J=10.9, 1.6Hz, 1H), 7.17 (ddd, J=9.2, 7.8, 3.3 Hz, 1H), 7.20 (dd, J=9.2, 7.8 Hz,1H), 5.27-5-19 (m, 1H), 4.61 (d, J=6.1 Hz, 2H), 3.91 (s, 3H), 2.15-1.98(m, 4H), 1.95-1.82 (m, 2H), 1.75-1.62 (m, 2H).

Example 64:N-[1-[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]ethyl]-2-methoxy-benzamide

N-[1-(4-Bromophenyl)ethyl]-2-methoxy-benzamide

To a solution of 4-bromo-α-methylbenzylamine (1.31 g, 6.57 mmol) andDIPEA (1.72 mL, 9.85 mmol) in anhydous THF (30 mL) was added2-methoxybenzoyl chloride (1.08 mL, 7.22 mmol) at 0° C. The reactionmixture was then allowed to return to room temperature and stirredovernight. The mixture was quenched with a saturated solution ofammonimum chloride (40 mL), extracted with EtOAc (3×20 mL). The combinedorganic extracts were washed with water (2×30 mL), brine (30 mL), driedover sodium sulfate, filtered and concentrated under reduced pressure.Further purification by flash column chromatography (heptane/EtOAc 90:10to 60:40) gave N-[1-(4-bromophenyl)ethyl]-2-methoxy-benzamide (2.07 g,6.19 mmol, 94% yield) as a white solid.

UPLC-MS (ES+, Short acidic): 1.96 min, m/z 336.1[M+2]⁺

2-Methoxy-N-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]benzamide

Following general procedure N,N-[1-(4-bromophenyl)ethyl]-2-methoxy-benzamide (261 mg, 0.78 mmol)afforded crude2-methoxy-N-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]benzamide(288 mg, 0.75 mmol, 97% yield).

UPLC-MS (ES⁺, Short acidic): 2.12 min, m/z 382.2 [M+H]⁺

N-[1-[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]ethyl]-2-methoxy-benzamide

Following general procedure D,2-methoxy-N-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]benzamide(139 mg, 0.36 mmol) and1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.30mmol) afforded, after further purification by flash columnchromatography (DCM/MeOH 100:0 to 95:5) and SCX,N-[1-[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]ethyl]-2-methoxy-benzamide(38.3 mg, 0.08 mmol, 25% yield).

UPLC-MS (ES⁺, Short acidic): 1.74 min, m/z 457.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.80 min, m/z 457.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.56 (d, J=7.9 Hz, 1H), 8.24 (s, 1H),7.69-7.62 (m, 3H), 7.60-7.54 (m, 2H), 7.50-7.44 (m, 1H), 7.18-7.13 (m,1H), 7.06-7.00 (m, 1H), 5.29-5.15 (m, 2H), 3.91 (s, 3H), 2.15-1.97 (m,4H), 1.95-1.82 (m, 2H), 1.75-1.61 (m, 2H), 1.51 (d, J=7.0 Hz, 3H).

Example 65:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]methyl]-2-methoxy-5-methyl-benzamide

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]methyl]-2-methoxy-5-methyl-benzamide

Following general procedure F,3-[4-(aminomethyl)-3-fluoro-phenyl]-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-4-amine(68 mg, 0.21 mmol) and 2-methoxy-5-methylbenzoic acid (35 mg, 0.21 mmol)gave, after further purification by flash column chromatography(DCM/MeOH 100:0 to 90:10) and filtration over Si—CO₃ SPE cartridge,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]methyl]-2-methoxy-5-methyl-benzamide(36 mg, 0.08 mmol, 36% yield).

UPLC-MS (ES+, Short acidic): 1.83 min, m/z 475.4 [M+H]⁺

UPLC-MS (ES+, Long acidic): 4.10 min, m/z 475.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.73 (t, J=5.8 Hz, 1H), 8.24 (s, 1H),7.61-7.40 (m, 4H), 7.29 (dd, J=8.3, 2.3 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H),5.28-5-18 (m, 1H), 4.60 (d, J=5.8 Hz, 2H), 3.89 (s, 3H), 2.27 (s, 3H),2.14-1.97 (m, 4H), 1.95-1.83 (m, 2H), 1.74-1.62 (m, 2H).

Example 66:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]methyl]-2-methoxy-benzamide

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]methyl]-2-methoxy-benzamide

Following general procedure F,3-[4-(aminomethyl)-3-fluoro-phenyl]-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-4-amine(73 mg, 0.22 mmol) and 2-methoxybenzoic acid (33 mg, 0.21 mmol) gave,after further purification by flash column chromatography (DCM/MeOH100:0 to 90:10) and filtration over Si—CO₃ SPE cartridge,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-phenyl]methyl]-2-methoxy-benzamide(15 mg, 0.03 mmol, 15% yield) as a beige solid.

UPLC-MS (ES+, Short acidic): 1.73 min, m/z 461.4 [M+H]⁺

UPLC-MS (ES+, Long acidic): 3.83 min, m/z 461.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.76 (t, J=6.0 Hz, 1H), 8.24 (s, 1H), 7.77(dd, J=7.7, 1.8 Hz, 1H), 7.57-7.41 (m, 4H), 7.19-7.15 (m, 1H), 7.07-7.02(m, 1H), 5.28-5-18 (m, 1H), 4.61 (d, J=6.0 Hz, 2H), 3.92 (s, 3H),2.15-1.97 (m, 4H), 1.95-1.83 (m, 2H), 1.74-1.63 (m, 2H).

Example 67:N-[1-[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]cyclopropyl]-2-methoxy-benzamide

N-[1-(4-Bromophenyl)cyclopropyl]-2-methoxy-benzamide

To a solution of 1-(4-bromophenyl)cyclopropanamine (534 mg, 2.52 mmol)and DIPEA (0.66 mL, 3.77 mmol) in anhydous THF (10 mL) was added2-methoxybenzoyl chloride (0.41 mL, 2.77 mmol) at 0° C. The reactionmixture was then allowed to return to room temperature and stirredovernight. The mixture was quenched with a saturated solution ofammonimum chloride (20 mL), extracted with EtOAc (3×10 mL). The combinedorganic extracts were washed with water (2×10 mL), brine (10 mL), driedover sodium sulfate, filtered and concentrated under reduced pressure.Further purification by flash column chromatography (heptane/EtOAc 90:10to 60:40) gave N-[1-(4-bromophenyl)cyclopropyl]-2-methoxy-benzamide (362mg, 1.05 mmol, 42% yield) as a white fluffy solid.

UPLC-MS (ES+, Short acidic): 1.98 min, m/z 346.1 [M]⁺

2-Methoxy-N-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]benzamide

Following general procedure N,N-[1-(4-bromophenyl)cyclopropyl]-2-methoxy-benzamide (261 mg, 0.75 mmol)afforded crude2-methoxy-N-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]benzamide(280 mg, 0.71 mmol, 95% yield)

UPLC-MS (ES⁺, Short acidic): 2.10 min, m/z 394.2 [M+H]⁺

N-[1-[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]cyclopropyl]-2-methoxy-benzamide

Following general procedure D,2-methoxy-N-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]benzamide(143 mg, 0.36 mmol) and1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.30mmol) afforded, after further purification by flash columnchromatography (DCM: MeOH 100:0 to 95:5) and SCX,N-[1-[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]cyclopropyl]-2-methoxy-benzamide(83 mg, 0.16 mmol, 53% yield).

UPLC-MS (ES⁺, Short acidic): 1.67 min, m/z 469.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.77 min, m/z 469.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.82 (s, 1H), 8.24 (s, 1H), 7.65-7.60 (m,3H), 7.49-7.45 (m, 1H), 7.42-7.40 (m, 2H), 7.18-7.13 (m, 1H), 7.06-7.00(m, 1H), 5.29-5.15 (m, 1H), 3.91 (s, 3H), 2.15-1.97 (m, 4H), 1.95-1.82(m, 2H), 1.75-1.61 (m, 2H), 1.35 (s, 4H).

Example 68-:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-naphthalene-1-carboxamide

[4-[[(2-Methoxynaphthalene-1-carbonyl)amino]methyl]phenyl]boronic acid

DMF (1 drop) was added to a cooled solution of2-methoxynaphthalene-1-carboxylic acid (0.17 mL, 0.84 mmol) and oxalylchloride (0.07 mL, 0.84 mmol) in DCM (10 mL) and stirred at roomtemperature for 1 h until a clear solution was obtained. To this wasadded carefully 4-aminomethylphenylboronic acid hydrochloride (150 mg,0.80 mmol) and N,N-diisopropylethylamine (0.41 mL, 2.40 mmol). Theresultant yellow suspension was stirred at room temperature overnight,diluted with further DCM (10 mL), quenched with sat NH₄Cl aq. (10 mL)and the layers separated. The aqueous layer was extracted with DCM (2×10mL). The combined organic layers were washed with brine, dried overMgSO₄, and concentrated in vacuo to give a cream solid. Furtherpurification by flash column chromatography on silica gel eluting with0-10% MeOH in DCM gave[4-[[(2-methoxynaphthalene-1-carbonyl)amino]methyl]phenyl]boronic acid(148 mg, 0.42 mmol, 52% yield) as a white solid.

LC-MS (ES⁺, method 3): 3.67 min, m/z 336.0 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-naphthalene-1-carboxamide

Following general procedure C,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (64 mg, 0.19 mmol)and [4-[[(2-methoxynaphthalene-1-carbonyl)amino]methyl]phenyl]boronicacid (65 mg, 0.19 mmol) gave, after further purification by flash columnchromatography on silica gel eluting with 0-8% MeOH/DCM,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-naphthalene-1-carboxamide(50 mg, 0.10 mmol, 52% yield).

LC-MS (ES⁺, method 4): 7.20 min, m/z 493.3 [M+H]⁺

¹H NMR (500 MHz, MeOH-d₄, δ): 8.24 (s, 1H), 7.97 (d, J=9.1 Hz, 1H),7.86-7.83 (m, 1H), 7.79-7.76 (m, 1H), 7.74-7.67 (m, 4H), 7.51-7.45 (m,2H), 7.37 (ddd, J=8.2, 6.9, 1.3 Hz, 1H), 5.29 (quint, J=7.5 Hz, 1H),4.77 (s, 2H), 4.01 (s, 3H), 2.20-2.13 (m, 4H), 2.05-1.95 (m, 2H),1.82-1.72 (m, 2H).

Example 69:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]isoquinoline-1-carboxamide

[4-[(Isoquinoline-1-carbonylamino)methyl]phenyl]boronic Acid

Following general procedure A, suspension of 4-aminomethylphenylboronicacid hydrochloride (88 mg, 0.47 mmol) and isoquinoline-1-carboxylic acid(100 mg, 0.57 mmol) afforded crude[4-[(isoquinoline-1-carbonylamino)methyl]phenyl]boronic acid (114 mg,0.26 mmol, 56% yield) as light brown crystals.

LC-MS (ES⁺, method 3): 3.16 min, m/z 307.0 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]isoquinoline-1-carboxamide

Following general procedure C,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (56 mg, 0.17 mmol)and [4-[(isoquinoline-1-carbonylamino)methyl]phenyl]boronic acid (47 mg,0.15 mmol) yieldedN-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]isoquinoline-1-carboxamide(25 mg, 0.05 mmol, 33% yield).

LC-MS (ES⁺, method 3): 4.26 min, m/z 463.9 [M+H]⁺

LC-MS (ES⁺, method 4): 8.45 min, m/z 464.2 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆, δ): 9.50 (t, J=6.3 Hz, 1H), 8.98 (dd, J=8.5,0.6 Hz, 1H), 8.58 (d, J=5.7 Hz, 1H), 8.23 (s, 1H), 8.09-8.03 (m, 2H),7.84 (ddd, J=8.2, 6.8, 1.3 Hz, 1H), 7.74 (ddd, J=8.2, 6.6, 1.3 Hz, 1H),7.68-7.63 (m, 2H), 7.60-7.55 (m, 2H), 5.27-5.19 (m, 1H), 4.65 (d, J=6.3Hz, 2H), 2.13-1.98 (m, 4H), 1.93-1.84 (m, 2H), 1.73-1.63 (m, 2H).

Example 70:—N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]quinoline-8-carboxamide

[4-[(Quinoline-8-carbonylamino)methyl]phenyl]boronic Acid

Following general procedure O, quinoline-8-carboxylic acid (81 mg, 0.47mmol) and 4-aminomethylphenylboronic acid hydrochloride (80 mg, 0.43mmol) gave [4-[(quinoline-8-carbonylamino)methyl]phenyl]boronic acid (56mg, 0.18 mmol, 43% yield).

LC-MS (ES⁺, method 3): 3.48 min, m/z 306.9 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]quinoline-8-carboxamide

Following general procedure C,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (67 mg, 0.20 mmol)and [4-[(quinoline-8-carbonylamino)methyl]phenyl]boronic acid (56 mg,0.18 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 5-10% MeOH in DCM,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]quinoline-8-carboxamide(13 mg, 0.03 mmol, 15% yield).

LC-MS (ES⁺, method 4): 8.03 min, m/z 464.0 [M+H]⁺

¹H NMR (500 MHz, CDCl₃, δ): 11.87-11.80 (m, 1H), 8.95-8.91 (m, 2H), 8.36(s, 1H), 8.31 (dd, J=8.2, 1.6 Hz, 1H), 8.00 (dd, J=8.2, 1.6 Hz, 1H),7.74-7.70 (m, 1H), 7.69-7.66 (m, 2H), 7.64-7.60 (m, 2H), 7.51 (dd,J=8.2, 4.4 Hz, 1H), 5.50-5.41 (br s, 2H), 5.35-5.26 (m, 1H), 4.92 (d,J=6.0 Hz, 2H), 2.21-2.12 (m, 4H), 2.03-1.92 (m, 2H), 1.76-1.69 (m, 2H).

Example 71:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-3-methoxy-naphthalene-2-carboxamide

[4-[[(3-methoxynaphthalene-2-carbonyl)amino]methyl]phenyl]boronic Acid

Following general procedure A, 4-aminomethylphenylboronic acidhydrochloride (228 mg, 1.21 mmol) and 3-methoxynaphthalene-2-carboxylicacid (300 mg, 1.48 mmol) gave after work-up[4-[[(3-methoxynaphthalene-2-carbonyl)amino]methyl]phenyl]boronic acid(327 mg, 0.98 mmol, 66% yield) as a white solid.

LC-MS (ES⁺, method 2): 3.42 min, m/z 336.0 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-3-methoxy-naphthalene-2-carboxamide

Following general procedure D,[4-[[(3-methoxynaphthalene-2-carbonyl)amino]methyl]phenyl]boronic acid(50 mg, 0.15 mmol) and1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (49 mg, 0.15 mmol)afforded, after purification by flash column chromatography on silicagel eluting with 0-6% MeOH in DCM,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-3-methoxy-naphthalene-2-carboxamide(20 mg, 0.03 mmol, 23% yield).

LC-MS (ES⁺, method 4): 8.80 min, m/z 493.2 [M+H]⁺

¹H NMR (500 MHz, CDCl₃, δ): 8.82 (s, 1H), 8.43 (t, J=5.6 Hz, 1H), 8.37(s, 1H), 7.94-7.90 (m, 1H), 7.78-7.74 (m, 1H), 7.71-7.67 (m, 2H),7.59-7.50 (m, 3H), 7.41 (ddd, J=8.2, 6.9, 1.1 Hz, 1H), 7.28-7.21 (m,1H), 5.57-5.44 (br s, 2H), 5.35-5.25 (m, 1H), 4.82 (d, J=5.6 Hz, 2H),4.07 (s, 3H), 2.21-2.14 (m, 4H), 2.03-1.92 (m, 2H), 1.77-1.69 (m, 2H).

Example72—N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]naphthalene-2-carboxamide

[4-[(Naphthalene-2-carbonylamino)methyl]phenyl]boronic Acid

Following general procedure O, 2-naphthoic acid (303 mg, 1.76 mmol) and4-aminomethyl phenyl boronic acid hydrochloride (300 mg, 1.60 mmol)afforded [4-[(naphthalene-2-carbonylamino)methyl]phenyl]boronic acid(327 mg, 1.07 mmol, 67% yield) as a white solid.

LC-MS (ES⁺, method 3): 3.86 min, m/z 306.0 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]naphthalene-2-carboxamide

Following general procedure C,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (90 mg, 0.27 mmol)and [4-[(naphthalene-2-carbonylamino)methyl]phenyl]boronic acid (100 mg,0.33 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-10% MeOH/DCM,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]naphthalene-2-carboxamide(115 mg, 0.25 mmol, 76% yield) as a brown solid.

LC-MS (ES⁺, method 4): 8.27 min, m/z 463.1 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆, δ): 9.29 (t, J=6.1 Hz, 1H), 8.54 (s, 1H), 8.23(s, 1H), 8.07-7.95 (m, 4H), 7.68-7.57 (m, 4H), 7.56-7.52 (m, 2H),5.26-5-19 (m, 1H), 4.62 (d, J=6.1 Hz, 2H), 2.13-1.97 (m, 4H), 1.93-1.83(m, 2H), 1.73-1.62 (m, 2H).

Example 73:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-phenyl]methyl]-2-methoxy-benzamide

(4-Bromo-2,6-difluoro-phenyl)methanamine

Following general procedure P, 4-bromo-2,6-difluorobenzonitrile (350 mg,1.61 mmol) yielded (4-bromo-2,6-difluoro-phenyl)methanamine (260 mg,1.17 mmol, 73% yield) as a yellow liquid.

LC-MS (ES⁺, method 2): 1.33 min, m/z 221.9 [M]⁺

N-[(4-Bromo-2,6-difluoro-phenyl)methyl]-2-methoxy-benzamide

Following general procedure O, 2-methoxybenzoic acid (196 mg, 1.29 mmol)and (4-bromo-2,6-difluoro-phenyl)methanamine (260 mg, 1.17 mmol) gave,after trituration with diethyl ether (5 mL),N-[(4-bromo-2,6-difluoro-phenyl)methyl]-2-methoxy-benzamide (250 mg,0.70 mmol, 60% yield) as a white solid.

LC-MS (ES⁺, method 3): 4.82 min, m/z 358.0 [M+H]⁺

N-[[2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-methoxy-benzamide

Following general procedure R,N-[(4-bromo-2,6-difluoro-phenyl)methyl]-2-methoxy-benzamide (250 mg,0.70 mmol) yielded crudeN-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-methoxy-benzamide(280 mg, 0.99 mmol, assumed quantitative) as a brown gum.

LC-MS (ES⁺, method 3): 3.78 min, m/z 322.07 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-phenyl]methyl]-2-methoxy-benzamide

Following general procedure C, a mixture ofN-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-methoxy-benzamide(121 mg, 0.30 mmol) and1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (82 mg, 0.25 mmol)afforded, after purification by flash column chromatography on silicagel eluting with 50-100% ethyl acetate in heptane,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2,6-difluoro-phenyl]methyl]-2-methoxy-benzamide(60 mg, 0.12 mmol, 48% yield) as a solid.

LC-MS (ES⁺, method 3): 4.45 min, m/z 479.1 [M+H]⁺

LC-MS (ES⁺, method 4): 8.48 min, m/z 479.1 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆, δ): 8.65 (t, J=5.7 Hz, 1H), 8.50 (s, 1H), 7.76(dd, J=7.9, 1.8 Hz, 1H), 7.48 (ddd, J=8.5, 7.3, 1.9 Hz, 1H), 7.40-7.32(m, 2H), 7.16 (d, J=8.2 Hz, 1H), 7.06-7.01 (m, 1H), 5.32-5.24 (m, 1H),4.64 (d, J=5.7 Hz, 2H), 3.90 (s, 3H), 2.18-2.08 (m, 2H), 2.07-1.97 (m,2H), 1.94-1.84 (m, 2H), 1.75-1.64 (m, 2H).

Example 74:N-[[4-[4-amino-1-(2-hydroxypropyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

1-(4-Amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)propan-2-ol

Following general procedure M,3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (200 mg, 0.77 mmol) and1-bromopropan-2-ol (282 mg, 2.03 mmol) afforded, after purification byflash column chromatography on silica gel eluting with 0-10% MeOH inDCM, 1-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)propan-2-ol (55 mg,0.16 mmol, 21% yield) as a white solid.

LC-MS (ES⁺, method 2): 2.34 min, m/z 320.0 [M+H]⁺

N-[[4-[4-Amino-1-(2-hydroxypropyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure C,[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid (59 mg, 0.21mmol) and 1-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)propan-2-ol(55 mg, 0.16 mmol) gave, after further purification by flash columnchromatography on silica gel eluting with 0-10% MeOH in EtOAc,N-[[4-[4-amino-1-(2-hydroxypropyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(39 mg, 0.09 mmol, 53% yield) as an off-white solid.

LC-MS (ES⁺, method 2): 1.72 min, m/z 433.2 [M+H]⁺

LC-MS (ES⁺, method 4): 5.42 min, m/z 433.1 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆, δ): 8.78 (t, J=6.1 Hz, 1H), 8.24 (s, 1H), 7.77(dd, J=7.6, 1.6 Hz, 1H), 7.67-7.62 (m, 2H), 7.54-7.46 (m, 3H), 7.18-7.14(m, 1H), 7.07-7.02 (m, 1H), 4.92 (d, J=5.0 Hz, 1H), 4.59 (d, J=6.1 Hz,2H), 4.34-4.4.26 (m, 1H), 4.19-4.10 (m, 2H), 3.91 (s, 3H), 1.08 (d,J=6.0 Hz, 3H).

Example 75:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-phenyl]methyl]-2-methoxy-benzamide

(4-Bromo-2-methoxy-phenyl)methanamine

Following general procedure Q, 4-bromo-2-methoxybenzonitrile (108 mg,0.51 mmol) gave (4-bromo-2-methoxy-phenyl)methanamine (67.2 mg, 0.31mmol, 61% yield).

¹H NMR (500 MHz, CDCl₃, δ): 7.12-7.02 (m, 2H), 7.00-6.96 (m, 1H), 3.84(s, 3H), 3.77 (s, 2H).

N-[(4-Bromo-2-methoxy-phenyl)methyl]-2-methoxy-benzamide

Following general procedure O, 2-methoxybenzoic acid (57 mg, 0.37 mmol)and (4-bromo-2-methoxy-phenyl)methanamine (67 mg, 0.31 mmol) gave crudeN-[(4-bromo-2-methoxy-phenyl)methyl]-2-methoxy-benzamide (55 mg, 0.16mmol, 51% yield).

LC-MS (ES⁺, method 3): 4.79 min, m/z 352.0 [M+H]⁺

2-Methoxy-N-[[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide

Following general procedure R,N-[(4-bromo-2-methoxy-phenyl)methyl]-2-methoxy-benzamide (54 mg, 0.16mmol) gave crude2-methoxy-N-[[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide(84 mg, 0.14 mmol, 92% yield) as a brown gum.

LC-MS (ES⁺, method 3): 5.05 min, m/z 398.1 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-phenyl]methyl]-2-methoxy-benzamide

Following general procedure C,2-methoxy-N-[[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide(57 mg, 0.14 mmol) and1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (52 mg, 0.16 mmol)afforded, after purification by flash column chromatography on silicagel eluting with 30-100% EtOAc in petrol ether,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxy-phenyl]methyl]-2-methoxy-benzamide(23 mg, 0.05 mmol, 34% yield).

LC-MS (ES⁺, method 2): 2.67 min, m/z 473.2 [M+H]⁺

¹H NMR (500 MHz, CDCl₃, δ): 8.44 (t, J=6.0 Hz, 1H), 8.41-8.31 (m, 1H),8.24 (dd, J=7.8, 1.6 Hz, 1H), 7.52-7.49 (m, 1H), 7.39 (ddd, J=8.3, 7.3,1.6 Hz, 1H), 7.23-7.19 (m, 2H), 7.11-7.06 (m, 1H), 7.00-6.99 (m, 1H),5.84-5.61 (m, 2H), 5.34-5.25 (m, 1H), 4.72 (d, J=6.0 Hz, 2H), 3.99 (s,3H), 3.98 (s, 3H), 2.22-2.13 (m, 4H), 2.11-1.94 (m, 2H), 1.78-1.68 (m,2H).

Example76—N-[[4-(4-amino-1-isobutyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

3-Iodo-1-isobutyl-pyrazolo[3,4-d]pyrimidin-4-amine

Following general procedure M,4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (400 mg, 1.53 mmol) and1-bromo-2-methylpropane (0.15 mL, 1.69 mmol) gave crude3-iodo-1-isobutyl-pyrazolo[3,4-d]pyrimidin-4-amine (126 mg, 0.38 mmol,25% yield).

LC-MS (ES⁺, method 3): 3.45 min, m/z 318.0 [M+H]⁺

N-[[4-(4-Amino-1-isobutyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

Following general procedure D,3-iodo-1-isobutyl-pyrazolo[3,4-d]pyrimidin-4-amine (120 mg, 0.38 mmol)and [4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid (98 mg, 0.34mmol) gave, after purification by flash column chromatography on silicagel eluting with 1% methanol in ethyl acetate,N-[[4-(4-amino-1-isobutyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide(42 mg, 0.09 mmol, 24% yield).

LC-MS (ES⁺, method 4): 6.49 min, m/z 431.2 [M+H]⁺

¹H NMR (500 MHz, CDCl₃, δ): 8.39 (s, 1H), 8.34-8.29 (m, 1H), 8.27 (dd,J=7.9, 1.9 Hz, 1H), 7.70-7.66 (m, 2H), 7.56-7.51 (m, 2H), 7.51-7.45 (m,1H), 7.14-7.09 (m, 1H), 7.02-6.98 (m, 1H), 5.53-5.43 (m, 2H), 4.77 (d,J=6.0 Hz, 2H), 4.25 (d, J=7.6 Hz, 2H), 3.96 (s, 3H), 2.46-2.36 (m, 1H),0.96 (d, J=6.6 Hz, 6H).

Example77—N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-methoxy-phenyl]methyl]-2-methoxy-benzamide

(4-Bromo-3-methoxy-phenyl)methanamine

Following general procedure Q, 4-bromo-3-methoxy-benzonitrile (212 mg,1.0 mmol) afforded (4-bromo-3-methoxy-phenyl)methanamine (135 mg, 0.62mmol, 62% yield).

¹H NMR (500 MHz, CDCl₃, δ): 7.47 (d, J=8.2 Hz, 1H), 6.92-6.89 (m, 1H),6.79 (dd, J=8.2, 1.9 Hz, 1H), 3.91 (s, 3H), 3.84 (s, 2H).

N-[(4-Bromo-3-methoxy-phenyl)methyl]-2-methoxy-benzamide

Following general procedure O, 2-methoxybenzoic acid (110 mg, 0.72 mmol)and (4-bromo-3-methoxy-phenyl)methanamine (130 mg, 0.60 mmol) gave,after further purification by flash column chromatography on silica geleluting 30-60% with EtOAc in petrol ether,N-[(4-bromo-3-methoxy-phenyl)methyl]-2-methoxy-benzamide (172 mg, 0.49mmol, 82% yield).

LC-MS (ES⁺, method 3): 4.55 min, m/z 351.9 [M+H]⁺

2-Methoxy-N-[[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide

Following general procedure R,N-[(4-bromo-3-methoxy-phenyl)methyl]-2-methoxy-benzamide (167 mg, 0.48mmol) gave, after purification by flash column chromatography on silicagel eluting with 1-7% MeOH in DCM), an inseparable 2:1 mixture of2-methoxy-N-[(3-methoxyphenyl)methyl]benzamide (50 mg, 0.18 mmol, 39%yield) and2-methoxy-N-[[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide(100 mg, 0.25 mmol, 53% yield).

LC-MS (ES⁺, method 2): 2.60 min, m/z 272.2 [M+H]⁺ and 2.96 min, m/z398.2 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-methoxy-phenyl]methyl]-2-methoxy-benzamide

Following general procedure D,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (46 mg, 0.14 mmol)and2-methoxy-N-[[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide(50 mg, 0.13 mmol) afforded, after purification by preparative HPLC(30-80% MeCN in H₂O),N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-methoxy-phenyl]methyl]-2-methoxy-benzamide(28 mg, 0.06 mmol, 47% yield) as an off-white solid.

LC-MS (ES⁺, method 4): 6.59 min, m/z 473.2 [M+H]⁺

¹H NMR (500 MHz, MeOD-d₄, δ): 8.19 (s, 1H), 7.91 (dd, J=7.6, 1.9 Hz,1H), 7.52 (ddd, J=8.2, 7.3, 1.9 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H),7.23-7.21 (m, 1H), 7.19-7.11 (m, 2H), 7.08 (td, J=7.5, 0.9 Hz, 1H), 5.25(quint, J=7.6 Hz, 1H), 4.71 (s, 2H), 3.99 (s, 3H), 3.86 (s, 3H),2.21-2.08 (m, 4H), 2.02-1.92 (m, 2H), 1.80-1.70 (m, 2H).

Example78—N-[[4-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

3-Iodo-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine

Following general procedure M,3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (535 mg, 2.03 mmol) and2-bromopropane (0.21 mL, 2.24 mmol) gave, after further purification byflash column chromatography on silica gel eluting with 1-10% MeOH inDCM, 3-iodo-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine (242 mg, 0.80mmol, 39% yield) as a pale yellow solid.

LC-MS (ES⁺, method 2): 3.04 min, m/z 304.0 [M+H]⁺

N-[[4-(4-Amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide

Following general procedure C,[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid (97 mg, 0.34mmol) and 3-iodo-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine (86 mg,0.28 mmol) gave, after purification by preparative HPLC (5-95% MeCN inH₂O with 0.1% ammonia),N-[[4-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide(42 mg, 0.10 mmol, 36% yield) as an off-white solid.

LC-MS (ES⁺, method 4): 6.59 min, m/z 417.3 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆, δ): 8.77 (t, J=6.2 Hz, 1H), 8.24 (s, 1H), 7.77(dd, J=7.6, 1.9 Hz, 1H), 7.66-7.62 (m, 2H), 7.53-7.46 (m, 3H), 7.18-7.14(m, 1H), 7.05 (td, J=7.6, 0.9 Hz, 1H), 5.06 (quint, J=6.9 Hz, 1H), 4.59(d, J=6.2 Hz, 2H), 3.91 (s, 3H), 1.49 (d, J=6.9 Hz, 6H).

Example79-N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-methyl-phenyl]methyl]-2-methoxy-benzamide

(4-Bromo-3-methyl-phenyl)methanamine

Following general procedure Q, 4-bromo-3-methylbenzonitrile (200 mg,1.02 mmol) gave (4-bromo-3-methyl-phenyl)methanamine (126 mg, 0.63 mmol,62% yield) as a white solid.

¹H NMR (500 MHz, CDCl₃, δ): 7.47 (d, J=8.2 Hz, 1H), 7.21-7.18 (m, 1H),6.99 (dd, J=8.2, 1.9 Hz, 1H), 3.80 (s, 2H), 2.39 (s, 3H).

N-[(4-Bromo-3-methyl-phenyl)methyl]-2-methoxy-benzamide

Following general procedure O, 2-methoxybenzoic acid (105 mg, 0.69 mmol)and (4-bromo-3-methyl-phenyl)methanamine (126 mg, 0.63 mmol) gaveN-[(4-bromo-3-methyl-phenyl)methyl]-2-methoxy-benzamide (146 mg, 0.27mmol, 43% yield).

LC-MS (ES⁺, method 3): 4.88 min, m/z 336.0 [M+H]⁺

2-Methoxy-N-[[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide

Following general procedure R,N-[(4-bromo-3-methyl-phenyl)methyl]-2-methoxy-benzamide (146 mg, 0.44mmol) gave crude2-methoxy-N-[[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide(162 mg, 0.30 mmol, 68% yield) as an brown gum.

LC-MS (ES⁺, method 2): 3.50 min, m/z 382.2 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-methyl-phenyl]methyl]-2-methoxy-benzamide

Following general procedure C,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (117 mg, 0.36mmol) and2-methoxy-N-[[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide(163 mg, 0.43 mmol) gave, after purification by preparative HPLC (5-95%MeCN in H₂O and 0.1% ammonia),N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-3-methyl-phenyl]methyl]-2-methoxy-benzamide(18 mg, 0.04 mmol, 11% yield) as a brown solid.

LC-MS (ES⁺, method 4): 7.39 min, m/z 457.4 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆, δ): 8.72 (t, J=6.0 Hz, 1H), 8.23 (s, 1H), 7.76(dd, J=7.8, 1.8 Hz, 1H), 7.48 (ddd, J=8.2, 7.6, 1.9 Hz, 1H), 7.37-7.29(m, 3H), 7.18-7.14 (m, 1H), 7.05 (td, J=7.5, 0.6 Hz, 1H), 5.27-5.19 (m,1H), 4.55 (d, J=6.0 Hz, 2H), 3.91 (s, 3H), 2.25 (s, 3H), 2.14-2.05 (m,2H), 2.04-1.95 (m, 2H), 1.91-1.80 (m, 2H), 1.73-1.62 (m, 2H).

Example 80:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-isopropyl-benzamide

[4-[[(2-Isopropylbenzoyl)amino]methyl]phenyl]boronic Acid

Following general procedure A, a suspension of4-aminomethylphenylboronic acid hydrochloride (1.41 g, 7.50 mmol) and2-isopropylbenzoic acid (1.51 g, 9.00 mmol) gave after work-up, crude[4-[[(2-isopropylbenzoyl)amino]methyl]phenyl]boronic acid (82 mg, 0.27mmol, 4% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.53 min, m/z 298.2 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-isopropyl-benzamide

Following general procedure D, a mixture of1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (75 mg, 0.23 mmol)and [4-[[(2-isopropylbenzoyl)amino]methyl]phenyl]boronic acid (81 mg,0.27 mmol) gave, after further purification by flash columnchromatography (DCM/MeOH 100:0 to 90:10),N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-isopropyl-benzamide(82 mg, 0.18 mmol, 79% yield) as a light beige foam.

UPLC-MS (ES⁺, Short acidic): 1.75 min, m/z 455.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.93 min, m/z 455.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.91 (t, J=6.0 Hz, 1H), 8.26 (s, 1H),7.69-7.62 (m, 2H), 7.56-7.48 (m, 2H), 7.43-7.36 (m, 2H), 7.34-7.28 (m,1H), 7.27-7.19 (m, 1H), 5.29-5.19 (m, 1H), 4.52 (d, J=6.0 Hz, 2H),3.32-3.18 (m, 1H), 2.15-1.97 (m, 4H), 1.95-1.82 (m, 2H), 1.76-1.62 (m,2H), 1.21 (s, 6H).

Example 81:N-[[4-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]benzofuran-2-carboxamide

[4-[(Benzofuran-2-carbonylamino)methyl]phenyl]boronic Acid

Following general procedure O, benzofuran-2-carboxylic acid (291 mg,1.76 mmol) and 4-aminomethylphenylboronic acid hydrochloride (300 mg,1.60 mmol) yielded [4-[(benzofuran-2-carbonylamino)methyl]phenyl]boronicacid (340 mg, 1.15 mmol, 72% yield) as a white solid

LC-MS (ES⁺, method 3): 3.11 min, m/z 296.0 [M+H]⁺

N-[[4-(4-Amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]benzofuran-2-carboxamide

Following general procedure C, a mixture of3-bromo-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-4-amine (85 mg, 0.31 mmol)and [4-[(benzofuran-2-carbonylamino)methyl]phenyl]boronic acid (111 mg,0.38 mmol) gave, after further purification by flash columnchromatography on silica gel eluting 0-5% MeOH in DCM,N-[[4-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]benzofuran-2-carboxamide(110 mg, 0.24 mmol, 75% yield) as a white solid.

LC-MS (ES⁺, method 2): 2.91 min, m/z 441.5 [M+H]⁺

LC-MS (ES⁺, method 4): 7.93 min, m/z 441.5 [M+H]⁺

¹H NMR (500 MHz, CDCl₃, δ): 8.36 (s, 1H), 7.73-7.66 (m, 3H), 7.56-7.52(m, 3H), 7.49-7.46 (m, 1H), 7.44-7.39 (m, 1H), 7.32-7.28 (m, 1H),7.10-7.03 (m, 1H), 5.57-5-44 (br s, 2H), 4.75 (d, J=6.3 Hz, 2H), 1.83(s, 9H).

Example 82:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-1,3-benzothiazole-2-carboxamide

[4-[(1,3-Benzothiazole-2-carbonylamino)methyl]phenyl]boronic acid

DMF (1 drop) was added to a cooled solution ofbenzothiazole-2-carboxylicacid (0.17 mL, 0.84 mmol) and oxalyl chloride(0.07 mL, 0.84 mmol) in DCM (10 mL), then stirred at rt for 1.5 h untila clear solution was observed. 4-Aminomethylphenylboronic acidhydrochloride (150 mg, 0.80 mmol) and N,N-diisopropylethylamine (0.41mL, 2.40 mmol) was carefully added. The resultant yellow suspensionstirred at rt overnight, diluted with further DCM (10 mL) and quenchedwith sat NH₄Cl aq (10 mL) and the layers separated. The aqueous wasextracted with DCM (2×10 mL). The combined organic layers were washedwith brine, dried over MgSO₄, and concentrated in vacuo to give a creamsolid. Further purification by flash column chromatography on silica geleluting 0-10% MeOH in DCM gave[4-[(1,3-benzothiazole-2-carbonylamino)methyl]phenyl]boronic acid (110mg, 0.35 mmol, 44% yield).

LC-MS (ES⁺, method 3): 3.95 min, m/z 313.0 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-1,3-benzothiazole-2-carboxamide

Following general procedure C,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (53 mg, 0.16 mmol)and [4-[(1,3-benzothiazole-2-carbonylamino)methyl]phenyl]boronic acid(50 mg, 0.16 mmol) gave, after purification by flash columnchromatography on silica gel eluting 0-8% MeOH/DCM,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-1,3-benzothiazole-2-carboxamide(50 mg, 0.11 mmol, 66% yield) as an off-white solid.

LC-MS (ES⁺, method 3): 8.58 min, m/z 470.0 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆, δ): 9.84 (t, J=6.3 Hz, 1H), 8.28-8.22 (m, 2H),8.18-8.13 (m, 1H), 7.68-7.57 (m, 4H), 7.56-7.51 (m, 2H), 5.26-5.19 (m,1H), 4.59 (d, J=6.3 Hz, 2H) 2.13-1.96 (m, 4H), 1.93-1.81 (m, 2H),1.72-1.61 (m, 2H).

Example 83:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]benzofuran-2-carboxamide

Following general procedure C,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (70 mg, 0.21 mmol)and [4-[(benzofuran-2-carbonylamino)methyl]phenyl]boronic acid (69 mg,0.23 mmol) gave, after purification by flash column chromatography onsilica gel (50-100% ethyl acetate in 40/60 petroleum ether),N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]benzofuran-2-carboxamide(50 mg, 0.11 mmol, 49% yield) as a white solid.

LC-MS (ES⁺, method 3): 4.13 min, m/z 453.1 [M+H]⁺

LC-MS (ES⁺, method 4): 7.50 min, m/z 453.5 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆, δ): 9.39 (t, J=6.2 Hz, 1H), 8.24 (s, 1H),7.82-7.78 (m, 1H), 7.70-7.67 (m, 1H), 7.66-7.63 (m, 2H), 7.62-7.60 (m,1H), 7.54-7.51 (m, 2H), 7.51-7.46 (m, 1H), 7.38-7.33 (m, 1H), 5.23(quint, J=7.4 Hz, 1H), 4.58 (d, J=6.2 Hz, 2H), 2.14-2.00 (m, 4H),1.94-1.83 (m, 2H), 1.74-1.63 (m, 2H).

Example 84:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]benzothiophene-2-carboxamide

[4-[(Benzothiophene-2-carbonylamino)methyl]phenyl]boronic Acid

Following general procedure O, benzothiophene-2-carboxylic acid (103 mg,0.58 mmol) and 4-aminomethylphenylboronic acid hydrochloride (98 mg,0.52 mmol) yielded[4-[(benzothiophene-2-carbonylamino)methyl]phenyl]boronic acid (106 mg,0.34 mmol, 65% yield).

LC-MS (ES⁺, method 3): 3.89 min, m/z 312.0 [M+H]⁺

N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]benzothiophene-2-carboxamide

Following general procedure C, a mixture of1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (65 mg, 0.20 mmol)and [4-[(benzothiophene-2-carbonylamino)methyl]phenyl]boronic acid (68mg, 0.22 mmol) gave, after further purification by flash columnchromatography on silica gel eluting 50-100% EtOAc in 40:60 petroleumether,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]benzothiophene-2-carboxamide(28 mg, 0.06 mmol, 30% yield).

LC-MS (ES⁺, method 3): 4.30 min, m/z 469.0 [M+H]⁺

LC-MS (ES⁺, method 4): 7.60 min, m/z 469.0 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆, δ): 9.40 (t, J=6.0 Hz, 1H), 8.23 (s, 1H), 8.17(s, 1H), 8.05-8.01 (m, 1H), 7.98-7.94 (m, 1H), 7.68-7.62 (m, 2H),7.55-7.50 (m, 2H), 7.49-7.41 (m, 2H), 5.26-5.19 (m, 1H), 4.58 (d, J=6.0Hz, 2H), 2.14-1.99 (m, 4H), 1.94-1.83 (m, 2H), 1.73-1.62 (m, 2H).

Example 85:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]quinoline-2-carboxamide

[4-[(Quinoline-2-carbonylamino)methyl]phenyl]boronic Acid

Following general procedure O, quinoline-2-carboxylic acid (63 mg, 0.36mmol) and 4-aminomethylphenylboronic acid hydrochloride (62 mg, 0.33mmol) gave crude [4-[(quinoline-2-carbonylamino)methyl]phenyl]boronicacid (63 mg, 0.21 mmol, 63% yield).

LC-MS (ES⁺, method 3): 3.88 min, m/z 307.0 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]quinoline-2-carboxamide

Following general procedure C,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (75 mg, 0.23 mmol)and [4-[(quinoline-2-carbonylamino)methyl]phenyl]boronic acid (63 mg,0.21 mmol) gave after purification by flash column chromatography onsilica gel,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]quinoline-2-carboxamide(16 mg, 0.03 mmol, 17% yield).

LC-MS (ES⁻, method 4): 8.55 min, m/z 462.0 [M−H]⁻

¹H NMR (500 MHz, CDCl₃, δ): 8.72 (t, J=5.9 Hz, 1H), 8.36-8.29 (m, 3H),8.08-8.04 (m, 1H), 7.91-7.84 (m, 1H), 7.77-7.71 (m, 1H), 7.69-7.64 (m,2H), 7.62-7.54 (m, 1H), 7.56-7.51 (m, 2H), 5.89-5.82 (br s, 2H),5.32-5.21 (m, 1H), 4.78 (d, J=5.9 Hz, 2H), 2.20-2.09 (m, 4H), 1.99-1.88(m, 2H), 1.74-1.63 (m, 2H).

Example 86:N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide

N-[(4-Bromophenyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide

HATU (485 mg, 1.28 mmol) was added in one portion to a mixture of3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid hydrochloride (250mg, 1.16 mmol), 4-bromobenzylamine hydrochloride (774 mg, 3.48 mmol) andtriethylamine (0.81 mL, 5.80 mmol) in anhydrous DMF (5 mL), cooled at 0°C. The reaction mixture was stirred at 0° C. for 1 h and thenpartitioned between brine and ethyl acetate. The organic layer waswashed with brine (×2), dried over sodium sulfate, filtered andconcentrated under reduced pressure. Further purification by flashcolumn chromatography on silica gel eluting 0-50% ethyl acetate in 40/60petroleum ether yieldedN-[(4-bromophenyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide(220 mg, 0.63 mmol, 55% yield).

LC-MS (ES+, method 2): 2.87 min, m/z 349.4 [M+H]⁺

N-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide

Following general procedure R,N-[(4-bromophenyl)methyl]-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide(205 mg, 0.59 mmol) afforded crudeN-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide(205 mg, 0.52 mmol, 88% yield) as a black solid.

LC-MS (ES⁺, method 2): 3.10 min, m/z 395.6 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide

Following general procedure C,N-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide(101 mg, 0.26 mmol) and1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (70 mg, 0.21 mmol)afforded, after further purification by flash column chromatography onsilica gel eluting 0-2% MeOH in EtOAc,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide(25 mg, 0.05 mmol, 25% yield) as a white solid.

LC-MS (ES⁺, method 3): 3.11 min, m/z 470.2 [M+H]⁺

LC-MS (ES⁺, method 4): 6.72 min, m/z 470.2 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆, δ): 8.56 (t, J=6.2 Hz, 1H), 8.24 (s, 1H),7.60-7.56 (m, 2H), 7.39-7.34 (m, 2H), 6.82 (dd, J=8.0, 1.4 Hz, 1H), 6.73(td, J=7.6, 1.4 Hz, 1H), 6.61 (dd, J=7.9, 1.6 Hz, 1H), 6.56-6.51 (m,1H), 5.90-5.85 (m, 1H), 5.23 (quint, J=7.4 Hz, 1H), 4.62 (dd, J=6.8, 2.8Hz, 1H), 4.45 (dd, J=15.3, 6.3 Hz, 1H), 4.37 (dd, J=15.3, 6.3 Hz, 1H),3.47 (dt, J=12.0, 3.0 Hz, 1H), 3.31-3.27 (m, 1H), 2.13-2.00 (m, 4H),1.95-1.83 (m, 2H), 1.74-1.63 (m, 2H).

Example 87:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-1,3-benzoxazole-7-carboxamide

[4-[(1,3-Benzoxazole-7-carbonylamino)methyl]phenyl]boronic Acid

Following general procedure O, 4-aminomethylphenylboronic acidhydrochloride (281 mg, 1.50 mmol) and 1,3-benzoxazole-7-carboxylic acid(204 mg, 1.25 mmol) gave crude[4-[(1,3-benzoxazole-7-carbonylamino)methyl]phenyl]boronic acid (227 mg,0.66 mmol, 53% yield) a pale yellow/orange solid.

LC-MS (ES⁺, method 3): 3.02 min, m/z 297.1 [M+H]⁺

N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-1,3-benzoxazole-7-carboxamide

Following general procedure C,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (79 mg, 0.24 mmol)and [4-[(1,3-benzoxazole-7-carbonylamino)methyl]phenyl]boronic acid (71mg, 0.24 mmol) afforded, after purification by flash columnchromatography on silica gel eluting 0-15% MeOH in DCM,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-1,3-benzoxazole-7-carboxamide(11 mg, 0.02 mmol, 10% yield).

LC-MS (ES⁺, method 2): 2.18 min, m/z 454.0 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆, δ): 8.90 (s, 1H), 8.24 (s, 1H), 8.01-7.96 (m,1H), 7.87-7.83 (m, 1H), 7.67-7.63 (m, 2H), 7.58-7.50 (m, 3H), 5.26-5.19(m, 1H), 4.66-4.62 (m, 2H), 2.13-1.97 (m, 4H), 1.94-1.83 (m, 2H),1.74-1.63 (m, 2H).

Example 88:N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-1H-indole-2-carboxamide

[4-[(1H-Indole-2-carbonylamino)methyl]phenyl]boronic Acid

Following general procedure O, 1H-indole-2-carboxylic acid (250 mg, 1.55mmol) and 4-aminomethylphenylboronic acid hydrochloride (291 mg, 1.55mmol) gave, after further purification by flash column chromatography onsilica gel eluting 0-20% MeOH in EtOAc,[4-[(1H-indole-2-carbonylamino)methyl]phenyl]boronic acid (124 mg, 0.42mmol, 27%).

LC-MS (ES⁺, method 3): 3.76 min, m/z 295.0 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-1H-indole-2-carboxamide

Following general procedure C,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.30mmol) and [4-[(1H-indole-2-carbonylamino)methyl]phenyl]boronic acid (107mg, 0.36 mmol) afforded, after purification by flash columnchromatography on silica gel eluting 0-10% MeOH/EtOAc,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-1H-indole-2-carboxamide(56 mg, 0.12 mmol, 41% yield) as a pale brown powder.

LC-MS (ES+, method 4): 7.67 min, m/z 452.2 [M+H]⁺

¹H NMR (500 MHz, DMSO-d₆, δ): 11.63 (s, 1H), 9.11 (t, J=6.2 Hz, 1H),8.23 (s, 1H), 7.67-7.60 (m, 3H), 7.54-7.50 (m, 2H), 7.45-7.42 (m, 1H),7.22-7.16 (m, 2H), 7.06-7.01 (m, 1H), 5.26-5-19 (m, 1H), 4.60 (d, J=6.2Hz, 2H), 2.13-1.98 (m, 4H), 1.93-1.84 (m, 2H), 1.73-1.63 (m, 2H).

Example 89:N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methyl-phenyl]methyl]-2-methoxy-benzamide

(4-Bromo-2-methyl-phenyl)methanamine

Following general procedure P, 4-bromo-2-methyl-benzonitrile (1.0 g,5.10 mmol) gave crude (4-bromo-2-methyl-phenyl)methanamine (1.4 g, 6.87mmol, assumed quantitative yield), which was used without furtherpurification.

UPLC-MS (ES⁺, Short acidic): 1.04 min, m/z 201.8 [M+2]⁺

N-[(4-Bromo-2-methyl-phenyl)methyl]-2-methoxy-benzamide

To a suspension of (4-bromo-2-methyl-phenyl)methanamine (1.02 g, 5.10mmol) and DIPEA (2.66 mL, 15.29 mmol) in anhydrous THF (20 mL), cooledat 0° C. under a nitrogen atmosphere, was added 2-methoxybenzoylchloride (0.83 mL, 5.61 mmol). The reaction mixture was stirredovernight at room temperature, quenched with a saturated aqueoussolution of ammonium chloride and then extracted with EtOAc (×3). Thecombined organics were washed with brine, dried over Na₂SO₄ and filteredthen concentrated under reduced pressure. Further purification by flashcolumn chromatography on silica gel eluting with 0-30% EtOAc in heptanegave N-[(4-bromo-2-methyl-phenyl)methyl]-2-methoxy-benzamide (0.83 g,2.49 mmol, 49% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.85 min, m/z 336.1 [M+2]⁺

2-Methoxy-N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide

Following general procedure R,N-[(4-bromo-2-methyl-phenyl)methyl]-2-methoxy-benzamide (0.83 g, 2.49mmol) gave crude2-methoxy-N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide(1.20 g, 3.22 mmol, assumed quantitative yield) as a black oil, whichwas used without further purification.

UPLC-MS (ES⁺, Short acidic): 1.95 min, m/z 382.2 [M+H]⁺

N-[[4-(4-Amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methyl-phenyl]methyl]-2-methoxy-benzamide

Following general procedure D,1-cyclopentyl-3-iodo-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.15 mmol)and2-methoxy-N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide(139 mg, 0.36 mmol) gave, after purification by flash columnchromatography on silica gel eluting with 50-100% EtOAc in heptane,N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methyl-phenyl]methyl]-2-methoxy-benzamide(18 mg, 0.04 mmol, 25% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.61 min, m/z 457.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 4.07 min, m/z 457.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.64 (t, J=5.9 Hz, 1H), 8.22 (s, 1H), 7.75(dd, J=7.7, 1.8 Hz, 1H), 7.51-7.46 (m, 4H), 7.18-7.15 (m, 1H), 7.05 (td,J=7.5, 0.9 Hz, 1H), 5.22 (quint, J=7.4 Hz, 1H), 4.54 (d, J=5.9 Hz, 2H),3.91 (s, 3H), 2.42 (s, 3H), 2.10-2.00 (m, 4H), 1.93-1.86 (m, 2H),1.74-1.65 (m, 2H).

Example 90:N-[[4-[4-Amino-1-(2,2,2-trifluoroethyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

N-[[4-[4-Amino-1-(2,2,2-trifluoroethyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

To a solution ofN-[[4-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]methyl]-2-methoxy-benzamide(120 mg, 0.32 mmol) in DMF (3 mL) were added1,1,1-trifluoro-2-iodoethane (87.5 mg, 0.42 mmol) and cesium carbonate(261 mg, 3.34 mmol). The reaction mixture was heated to 85° C. andstirred for 16 h. The reaction mixture was poured into brine andextracted with DCM. The combined organic extracts were filtered over ahydrophobic frit and concentrated under reduced pressure. Furtherpurification by reverse phase column chromatography (water/MeCN 95:5 to40:60) followed by flash column chromatography on silica gel elutingwith 0-5% MeOH in DCM and recrystallization from MeOH gave the titlecompound (23 mg, 0.05 mmol, 16% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.48 min, m/z 457.1 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.39 min, m/z 457.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.79 (t, J=6.0 Hz, 1H), 8.33 (s, 1H), 7.78(dd, J=7.6, 1.7 Hz, 1H), 7.67 (d, J=8.1 Hz, 2H), 7.55-7.48 (m, 3H), 7.17(d, J=8.3 Hz, 1H), 7.06 (t, J=7.5 Hz, 1H), 5.28 (q, J=9.0 Hz, 2H), 4.61(d, J=5.8 Hz, 2H), 3.92 (s, 3H).

Example 91:N-[[4-[4-amino-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(isomer 1)

8-Methyl-1,4-dioxaspiro[4.5]decan-8-ol

To a solution of 1,4-cyclohexanedione monoethylene acetal (6.00 g, 38.4mmol) in THF (48 mL) at 0° C. was added bromo(methyl)magnesium indiethyl ether (3 M, 19.2 mL, 42.26 mmol) under a nitrogen atmosphere.The reaction mixture was allowed to stir at room temperature for 2 h andthen quenched with a saturated NH₄Cl solution. Water was added and themixture was extracted with DCM. The combined organic extracts were driedover Na₂SO₄, filtered and concentrated under reduced pressure to give8-methyl-1,4-dioxaspiro[4.5]decan-8-ol (5.82 g, 27.7 mmol, 72% yield),which was used without further purification.

¹H NMR (400 MHz, CDCl₃, δ): 4.01-3.93 (m, 4H), 1.93-1.86 (m, 4H),1.73-1.68 (m 4H), 1.29 (s, 3H), 1.15 (s, 1H).

4-Hydroxy-4-methyl-cyclohexanone

To a solution of 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol (11.78 g, 68.4mmol) in THF (50 mL) was added aqueous HCl (1 M, 205 mL, 205.2 mmol).The reaction mixture was allowed to stir overnight at room temperature.Then, a saturated solution of Na₂CO₃ was added and the mixture extractedwith DCM. The combined organic extracts were dried over Na₂SO₄, filteredand concentrated under reduced pressure to afford crude4-hydroxy-4-methyl-cyclohexanone (6.18 g, 48.2 mmol, 71% yield).

¹H NMR (400 MHz, CDCl₃, δ): 2.70-2.61 (m, 2H), 2.21-2.14 (m, 2H),1.94-1.87 (m, 2H), 1.83-1.75 (m, 2H), 1.31 (s, 3H), 1.23 (s, 1H).

tert-Butyl N-[(4-hydroxy-4-methyl-cyclohexylidene)amino]carbamate

To a solution of 4-hydroxy-4-methyl-cyclohexanone (6.14 g, 47.88 mmol)in MeOH (60 mL) was added tert-butyl carbazate (6.64 g, 50.28 mmol). Thereaction mixture was stirred at room temperature for 2 days. Then, thesolvent was removed under reduced pressure and the obtained residuedissolved in DCM, washed with water, dried over Na₂SO₄ and concentratedunder reduced pressure. Further purification by flash columnchromatography on silica gel eluting with 0-100% EtOAc in heptanefollowed by column chromatography on silica gel eluting with 0-10% MeOHin DCM and recrystallization from ether and column chromatography onsilica gel eluting with 0-100% EtOAc in DCM gave tert-butylN-[(4-hydroxy-4-methyl-cyclohexylidene)amino]carbamate (1.39 g, 2.76mmol, 6% yield) as a solid.

UPLC-MS (ES⁺, Short acidic): 3.50 min, m/z 243.2 [M+H]⁺

5-Amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carbonitrile(isomers 1 and 2)

To a solution of tert-butylN-[(4-hydroxy-4-methyl-cyclohexylidene)amino]carbamate (400 mg, 1.65mmol) in THF (8 mL) was added borane-tetrahydrofuran (1:1) (1 M in THF,3.30 mL, 3.30 mmol) at 0° C. The reaction mixture was allowed to returnto room temperature and stirred for 16 hours. The reaction was quenchedwith MeOH (3 mL) and all volatiles were removed under reduced pressure.Hydrogen chloride in dioxane (4 M, 4.13 mL, 16.51 mmol) was added andthe reaction mixture allowed to stir for 1 hour at room temperature. Allvolatiles were removed under reduce pressure. The residue was dissolvedin EtOH and triethylamine (0.79 mL, 5.70 mmol) and2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (300 mg, 1.14mmol) were added. The reaction mixture was allowed to stir at roomtemperature overnight. Water was added and the mixture extracted withDCM. The combined extracts were filtered over a hydrophobic frit andconcentrated under reduced pressure. Further purification by flashcolumn chromatography on silica gel eluting with 55% EtOAc in heptanegave5-amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carbonitrile(isomer 1: 246 mg, 0.65 mmol, 57% yield over three steps) and furtherelution with 0-8% MeOH in DCM afforded5-amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carbonitrile(isomer2, 132 mg, 0.35 mmol, 31% yield over 3 steps).

UPLC-MS (ES⁺, Short acidic, isomer 1): 1.63 min, m/z 376.9 [M+2]⁺

UPLC-MS (ES⁺, Short acidic, isomer 2): 1.70 min, m/z 374.9 [M]⁺

4-[4-Amino-3-(4-bromophenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-cyclohexanol(Isomer 1)

Following general procedure S,5-amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carbonitrile(isomer 1, 100 mg, 0.27 mmol) afforded, after purification by flashcolumn chromatography on silica gel eluting with 2-6% MeOH in DCM,4-[4-amino-3-(4-bromophenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-cyclohexanol(40 mg, 0.10 mmol, 37% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.37 min, m/z 403.9 [M+2]⁺

N-[[4-[4-Amino-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(isomer 1)

Following general procedure K,4-[4-amino-3-(4-bromophenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-cyclohexanol(isomer 1, 40 mg, 0.10 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (40 mg, 0.15 mmol)gave, after purification by flash column chromatography on silica geleluting with 4-6% MeOH in DCM, followed by reverse phase chromatography(water/MeCN 70:30 to 65:35),N-[[4-[4-amino-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(isomer 1, 6 mg, 0.01 mmol, 12% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.33 min, m/z 487.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.95 min, m/z 487.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.78 (t, J=6.1 Hz, 1H), 8.23 (s, 1H), 7.78(dd, J=7.6, 1.7 Hz, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.54-7.46 (m, 3H), 7.17(d, J=8.3 Hz, 1H), 7.09-7.02 (m, 1H), 4.70-4.60 (m, 1H), 4.59 (d, J=6.1Hz, 2H), 4.20 (s, 1H), 3.92 (s, 3H), 2.44-2.32 (m, 2H), 1.74-1.60 (m,4H), 1.60-1.47 (m, 2H), 1.18 (s, 3H).

Example 92:N-[[4-[4-Amino-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(isomer 2)

4-[4-Amino-3-(4-bromophenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-cyclohexanol(Isomer 2)

Following general procedure S,5-amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carbonitrile(isomer 2, 100 mg, 0.27 mmol) gave, after purification by flash columnchromatography on silica gel eluting with 4-9% MeOH in DCM,4-[4-amino-3-(4-bromophenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-cyclohexanol(isomer 2, 41 mg, 0.10 mmol, 38% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.39 min, m/z 402.0 [M]⁺

N-[[4-[4-Amino-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(isomer 2)

Following general procedure K,4-[4-amino-3-(4-bromophenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-cyclohexanol(isomer 2, 40 mg, 0.10 mmol) and potassiumtrifluoro-[[(2-methoxybenzoyl)amino]methyl]boranuide (54 mg, 0.20 mmol)gave, after purification by flash column chromatography on silica geleluting with 5-8% MeOH in DCM followed by further purification withreverse phase chromatography (water/MeCN 70:30 to 65:35),N-[[4-[4-amino-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(isomer 2, 7 mg, 0.02 mmol, 15% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.30 min, m/z 487.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.89 min, m/z 487.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.88 (t, J=6.1 Hz, 1H), 8.27 (s, 1H), 7.78(dd, J=7.7, 1.7 Hz, 1H), 7.64 (d, J=8.1 Hz, 2H), 7.54-7.46 (m, 3H), 7.17(d, J=8.2 Hz, 1H), 7.08-7.02 (m, 1H), 4.75-4.64 (m, 1H), 4.59 (d, J=6.1Hz, 2H), 3.92 (s, 3H), 2.15-1.95 (m, 2H), 1.95-1.82 (m, 2H), 1.78-1.68(m, 2H), 1.68-1.54 (m, 2H), 1.24 (s, 3H).

Example 93:N-[[4-[4-Amino-1-(2,2,2-trifluoroethyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

5-Amino-3-(4-bromophenyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carbonitrile

To a solution of 2,2,2-trifluoroethyl hydrazine (465 mg, 2.85 mmol) inEtOH (10 mL) was added triethylamine (1.1 mL, 7.60 mmol). The reactionmixture was stirred at room temperature for 10 min before2-[(4-bromophenyl)-methoxy-methylene]propanedinitrile (500 mg, 1.90mmol) was added. The reaction mixture was heated to 95° C. and allowedto stir for 16 hours. The reaction mixture was diluted with DCM and themixture washed with saturated NH₄Cl solution, water and brine. Thecombined organic extracts were filtered through a hydrophobic frit andconcentrated under reduced pressure. Further purification by flashcolumn chromatography on silica gel eluting with 0-100% EtOAc in heptanegave5-amino-3-(4-bromophenyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carbonitrile(568 mg, 1.65 mmol, 87% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.78 min, m/z 436.8 [M+H]⁺

3-(4-Bromophenyl)-1-(2,2,2-trifluoroethyl)pyrazolo[3,4-d]pyrimidin-4-amine

A solution of5-amino-3-(4-bromophenyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carbonitrile(150 mg, 0.43 mmol) in formamide (0.75 mL, 22.17 mmol) was stirredovernight at 185° C. The reaction mixture was cooled to roomtemperature, diluted with water and extracted with EtOAc. The combinedorganics were washed with sat. NaHCO₃ solution, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give3-(4-bromophenyl)-1-(2,2,2-trifluoroethyl)pyrazolo[3,4-d]pyrimidin-4-amine(161 mg, 0.43 mmol, quantitative yield), which was used without furtherpurification.

¹H NMR (400 MHz, DMSO-d₆, δ): 8.33 (s, 1H), 7.76 (d, J=8.6 Hz, 2H), 7.63(d, J=8.6 Hz, 2H), 5.28 (q, J=9.1 Hz, 2H).

N-[[4-[4-Amino-1-(2,2,2-trifluoroethyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure K,3-(4-bromophenyl)-1-(2,2,2-trifluoroethyl)pyrazolo[3,4-d]pyrimidin-4-amine(105 mg, 0.28 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (162 mg,0.56 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-5% MeOH in DCM,N-[[4-[4-amino-1-(2,2,2-trifluoroethyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(15 mg, 0.03 mmol, 11% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.59 min, m/z 475.1 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.63 min, m/z 475.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.88 (t, J=6.0 Hz, 1H), 8.32 (s, 1H), 7.67(d, J=8.2 Hz, 2H), 7.55-7.52 (m, 3H), 7.38-7.32 (m, 1H), 7.20 (dd,J=9.1, 4.3 Hz, 1H), 5.27 (q, J=9.0 Hz, 2H), 4.60 (d, J=6.0 Hz, 2H), 3.91(s, 3H).

Example 94:N-[[4-[4-Amino-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(isomer 1)

Following general procedure K,4-[4-amino-3-(4-bromophenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-cyclohexanol(isomer 1, 30 mg, 0.07 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (32 mg,0.11 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-6% MeOH in DCM and further purification byreverse phase (water/MeCN, 100:0 to 65:35),N-[[4-[4-amino-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(isomer 1, 3 mg, 0.01 mmol, 9% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.38 min, m/z 505.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.07 min, m/z 505.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.87 (t, J=5.8 Hz, 1H), 8.22 (s, 1H), 7.65(d, J=8.1 Hz, 2H), 7.55-7.47 (m, 3H), 7.35 (ddd, J=9.0, 8.0, 3.3 Hz,1H), 7.19 (dd, J=9.1, 4.3 Hz, 1H), 4.70-4.59 (m, 1H), 4.59 (d, J=6.1 Hz,2H), 4.19 (s, 1H), 3.91 (s, 3H), 2.46-2.30 (m, 2H), 1.73-1.59 (m, 4H),1.59-1.41 (m, 2H), 1.17 (s, 3H).

Example 95:N-[[4-[4-Amino-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide-(isomer2)

Following general procedure K,4-[4-amino-3-(4-bromophenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-methyl-cyclohexanol(isomer 2, 3 mg, 0.07 mmol) and potassiumtrifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]boranuide (32 mg,0.11 mmol) gave, after purification by flash column chromatography onsilica gel eluting with 0-10% MeOH in DCM, followed by reverse phasechromatography (water/MeCN 100:0 to 67:33),N-[[4-[4-amino-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(isomer 2, 4 mg, 0.01 mmol, 12% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.34 min, m/z 505.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.01 min, m/z 505.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆, δ): 8.87 (t, J=6.0 Hz, 1H), 8.24 (s, 1H), 7.64(d, J=8.1 Hz, 2H), 7.56-7.47 (m, 3H), 7.39-7.31 (m, 1H), 7.20 (dd,J=9.1, 4.3 Hz, 1H), 4.75-4.62 (m, 1H), 4.58 (d, J=6.0 Hz, 2H), 4.46 (s,1H), 3.91 (s, 3H), 2.16-1.94 (m, 2H), 1.94-1.83 (m, 2H), 1.78-1.68 (m,2H), 1.68-1.55 (m, 2H), 1.24 (s, 3H)

Example 96: BTK^(WT) Binding Affinity

BTK^(WT) binding affinity of each compound tested was determined using atime-resolved fluorescence resonance energy transfer (TR-FRET)methodology. 2.5 nM Recombinant BTK^(WT) kinase, varying concentrationsof inhibitor, 2 nM LanthaScreen™ Eu anti-His Antibody and 15 nM KinaseTracer 236 was incubated in 1× LanthaScreen™ Kinase Buffer A for 5 h.Recombinant BTK kinase and all LanthaScreen™ components were purchasedfrom Invitrogen. Measurements were performed in a reaction volume of 30μL using half-area 96-well assay plates. The TR-FRET signal was read ona plate reader with an excitation wavelength of 340 nm and detectionwavelengths of 615 and 665 nm. Binding affinity was determined for eachcompound by measuring TR-FRET signal at various concentrations ofcompound and plotting the relative fluorescence units against theinhibitor concentration to estimate the IC₅₀ from log [Inhibitor] vsresponse using the Variable Slope model in Graphpad prism from Graphpadsoftware (SanDiego, Calif.).

Results of the BTK^(WT) Binding Affinity are shown below in Table 5

Table 5 shows the BTK^(WT) Binding affinity, as determined by the assaydescribed above, for compounds of formula (I), categorised based on theBTK IC₅₀ value of the compound as “A”, “B”, “C”, “D” and “E”.

IC₅₀: A≤10 nM; 10 nM<B≤100 nM; 100 nM<C≤1 μM; 1 μM<D≤10 μM; E>10 μM

Example 97: BTK^(C481S) Binding Affinity

BTK^(C481S) binding affinity of each compound tested was determinedusing a time-resolved fluorescence resonance energy transfer (TR-FRET)methodology. 5 nM Recombinant BTK^(WT) kinase, varying concentrations ofinhibitor, 2 nM LanthaScreen™ Eu anti-His Antibody and 30 nM KinaseTracer 236 was incubated in 1× LanthaScreen™ Kinase Buffer A for 5 h.Recombinant BTK^(C481S) kinase was purchased from SignalChem and allLanthaScreen™ components were purchased from Invitrogen. Measurementswere performed in a reaction volume of 30 μL using half-area 96-wellassay plates. The TR-FRET signal was read on a plate reader with anexcitation wavelength of 340 nm and detection wavelengths of 615 and 665nm. Binding affinity was determined for each compound by measuringTR-FRET signal at various concentrations of compound and plotting therelative fluorescence units against the inhibitor concentration toestimate the IC₅₀ from log [Inhibitor] vs response using the VariableSlope model in Graphpad prism from Graphpad software (SanDiego, Calif.).

Table 5 shows the BTK^(C481S) Binding affinity, as determined by theassay described above, for compounds of formula (I), categorised basedon the BTK IC₅₀ value of the compound as “A”, “B”, “C”, “D” and “E”.

IC₅₀: A≤10 nM; 10 nM<B≤100 nM; 100 nM<C≤1 μM; 1 μM<D≤10 μM; E>10 μM

Example 98: EGFR Binding Affinity

EGFR binding affinity was determined using a time-resolved fluorescenceresonance energy transfer (TR-FRET) methodology. 2.5 nM RecombinantEGFR, varying concentrations of inhibitor, 2 nM LanthaScreen™ Euanti-GST Antibody and 3 nM Kinase Tracer 199 was incubated in 1×LanthaScreen™ Kinase Buffer A for 5 h. Recombinant EGFR and allLanthaScreen™ components were purchased from Invitrogen. Measurementswere performed in a reaction volume of 30 μL using half-area 96-wellassay plates. The TR-FRET signal was read on a plate reader with anexcitation wavelength of 340 nm and detection wavelengths of 615 and 665nm. Binding affinity was determined for each compound by measuringTR-FRET signal at various concentrations of compound and plotting therelative fluorescence units against the inhibitor concentration toestimate the IC₅₀ from log [Inhibitor] vs response using the VariableSlope model in Graphpad prism from Graphpad software (SanDiego, Calif.).

Results of the EGFR binding affinity are shown in Table 5 below.

Table 5 shows the EGFR Binding Affinity, as determined by the assaydescribed above, for compounds of formula (I), categorised based on theEGFR IC₅₀ value of the compound as “A”, “B”, “C”, “D” and “E”.

IC₅₀: A≤10 nM; 10 nM<B≤100 nM; 100 nM<C≤1 μM; 1 μM<D≤10 μM; E>10 μM

Example 99: OCI-Ly10 Anti-Proliferative Activity

Compounds were assayed for effects on the growth of OCI-Ly10 human DLBCLcells that are dependent on NFκB signalling. OCI-Ly10 cells were grownin suspension in T225 flasks, centrifuged and re-suspended in 2.5% FBScontaining media. Cells were then plated at 7.5×10³ cells per well in96-well plates in varying concentrations of compound and incubated for72 h at 37° C. An additional plate of cells to be used as the Day 0 readwas seeded without compound addition, Resazurin was added to each well,incubated for 5 h and the fluorescence measured at 590 nm. After 72 h ofcompound treatment, Resazurin was added to each well of the compoundtreated plates, incubated for 5 h and the fluorescence measured at 590nm. The IC₅₀ was then calculated by subtracting the average Day 0 valuefrom each well value from the treated plates, each treatment was thencalculated as a percentage of the DMSO control and the percentagesplotted against the inhibitor concentration to estimate the IC₅₀ fromlog [Inhibitor] vs response using the Variable Slope model in Graphpadprism from Graphpad software (SanDiego, Calif.).

Table 5 shows the OCI-Ly10 anti-proliferative activity, as determined bythe assay described above, for compounds of formula (I), categorisedbased on the OCI-Ly10 IC₅₀ value of the compound as “A”, “B”, “C”, “D”and “E”.

IC₅₀: A≤10 nM; 10 nM<B≤100 nM; 100 nM<C≤1 μM; 1 μM<D≤10 μM; E>10 μM

“ND” in Table 5 means “Not Determined” and refers to compounds that havenot been tested in the indicated assay.

TABLE 5 BTK^(WT) BTK^(C481S) EGFR Proliferation Example IC₅₀ IC₅₀ IC₅₀OCI-Ly10-IC₅₀ 1 A A C B 2 C ND B D 3 C ND ND ND 4 A A C B 5 B B D C 6 CND C ND 7 A A D C 8 B A D D 9 C ND E C 10 C ND E C 11 A A D B 12 A A D B13 C ND E C 14 C ND D C 15 C ND D B 16 C ND D D 17 C ND D ND 18 B B D C19 A A C C 20 C ND D ND 21 A A D C 22 C ND D ND 23-isomer1  A A C C23-isomer2  A A C B 24 A A C B 25 A A C B 26 B A C C 27 B B C C 28 B B CC 29 A A C C 30 A A C ND 31 A A C B 32 A A C B 33-isomer 1 A A C B33-isomer 2 A A D B 33-isomer 2 A A C C 34 A A D B 35 A A B B 36 A A C C37 A A C C 38 A A B B 39 A A C B 40 A A C B 41 A A C C 42 A A D C 43 A AC B 44 A A D C 45 A A C C 46 B B C C 47 A A C C 48 B A D C 49 A A B B 50A A C C 51 A A B B 52 A A B B 53 B A D D 54 A A D C 55 B B D C 56 A A CC 57 C D D C 58 A A D C 59 B B D C 60 A A D C 61 A A D C 62 A A C B 63 AA D B 64 C C D D 65 A A D C 66 A A C B 67 D D D ND 68 C C D D 69 C C D D70 A A C C 71 C C ND ND 72 C ND ND ND 73 C B D ND 74 B B D C 75 A A D B76 A A C C 77 A A E B 78 A A D ND 79 A A D ND 80 D C D D 81 D ND ND D 82E C E ND 83 E ND ND ND 84 D ND ND ND 85 D ND ND ND 86 E E ND ND 87 D NDND ND 88 D C D ND 89 A A C C 90 B B E D 91 A A C C 92 A A C B 93 A A E C94 A A C B 95 A A C B

The following table, Table 6, provides values of the BTK bindingefficacy of a selection of compounds of the invention.

TABLE 6 BTK Binding ID. No. Name IC50 (nM)  4N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3- 0.8yl)phenyl]methyl]-5-fluoro-2-methoxy-benzamide 23-isomer 2N-[[4-[4-amino-1-(4-hydroxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3- 0.4yl]phenyl]methyl]-2-methoxy-benzamide 24N-[[4-[4-amino-1-[(1R*,3S*)-3-hydroxycyclopentyl]pyrazolo[3,4- 2.2d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 30N-[[4-[4-amino-1-[(1R,4R)-4-hydroxycyclopent-2-en-1- 1.4yl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 37N-[[4-[4-amino-1-(3-hydroxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3- 1.7yl]phenyl]methyl]-2-methoxy-benzamide 39N-[[4-[4-amino-1-(4-methoxycyclohexyl)pyrazolo[3,4-d]pyrimidin-3- 1.4yl]phenyl]methyl]-2-methoxy-benzamide 41 Ethyl 3-[4-amino-3-[4-[[(2- 1.2methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanecarboxylate 49N-[[4-(4-amino-1-cyclohex-2-en-1-yl-pyrazolo[3,4-d]pyrimidin-3- 0.4yl)phenyl]methyl]-2-methoxy-benzamide 51N-[[4-(4-amino-1-tert-butyl-pyrazolo[3,4-d]pyrimidin-3- 0.6yl)phenyl]methyl]-2-methoxy-benzamide 54N-[[4-[4-amino-1-[(1R,4R)-4-fluorocyclopent-2-en-1-yl]pyrazolo[3,4- 0.7d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 56N-[[4-[4-amino-1-[(1R)-indan-1-yl]pyrazolo[3,4-d]pyrimidin-3- 1.2yl]phenyl]methyl]-2-methoxy-benzamide 66N-[[4-(4-amino-1-cyclopentyl-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluoro-4.0 phenyl]methyl]-2-methoxy-benzamide

Throughout the description and claims of this specification, the words“comprise” and “contain” and variations of them mean “including but notlimited to”, and they are not intended to (and do not) exclude othermoieties, additives, components, integers or steps. Throughout thedescription and claims of this specification, the singular encompassesthe plural unless the context otherwise requires. In particular, wherethe indefinite article is used, the specification is to be understood ascontemplating plurality as well as singularity, unless the contextrequires otherwise.

Features, integers, characteristics, compounds, chemical moieties orgroups described in conjunction with a particular aspect, embodiment orexample of the invention are to be understood to be applicable to anyother aspect, embodiment or example described herein unless incompatibletherewith. All of the features disclosed in this specification(including any accompanying claims, abstract and drawings), and/or allof the steps of any method or process so disclosed, may be combined inany combination, except combinations where at least some of suchfeatures and/or steps are mutually exclusive. The invention is notrestricted to the details of any foregoing embodiments. The inventionextends to any novel one, or any novel combination, of the featuresdisclosed in this specification (including any accompanying claims,abstract and drawings), or to any novel one, or any novel combination,of the steps of any method or process so disclosed.

The reader's attention is directed to all papers and documents which arefiled concurrently with or previous to this specification in connectionwith this application and which are open to public inspection with thisspecification, and the contents of all such papers and documents areincorporated herein by reference.

The invention claimed is:
 1. A compound according to formula (I) orpharmaceutically acceptable salts thereof:

wherein A represents a ring selected from substituted or unsubstituted:phenyl, pyridyl, pyridazine, pyrimidine, or pyrazine, wherein whensubstituted A contains from 1 to 4 substituents independently selectedat each occurrence from: H, halo, C₁₋₆ alkyl, C₁₋₆ alkyl substitutedwith —OR¹, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl,C₃₋₈ cycloalkenyl, NR^(a)R^(b), —CN, acyl, —C(O)R^(a), —C(O)OR^(a),—SO₂R^(a), and —SO₃R^(a); D is selected from substituted orunsubstituted: C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkenyl, C₆₋₁₀aryl, 3 to 10 membered heterocycloalkyl, 3 to 10 memberedheterocycloalkenyl and 5 to 10 membered heteroaryl, wherein, whensubstituted, D contains from 1 to 9 substituents independently selectedat each occurrence from: halo, —OR^(c), —NR^(c)R^(d), ═O, —C(O)OR^(c),—OC(O)R^(e), —C(O)NR^(c)R^(d), —NR^(c)C(O)R^(e), C₁₋₆ haloalkyl, C₁₋₆alkyl substituted with —OR^(c), C₃₋₈ cycloalkyl, —SO₂R^(c), SO₃R^(c),and C(O)R^(c); one of X and Y is N and the other is C, wherein

represents a single or double bond and a single bond is present betweenN and X or Y when X or Y is N and a double bond is present between N andX or Y when X or Y is C; n is selected from 1 or 2; R¹ is a groupselected from a substituted or unsubstituted: C₃₋₈ cycloalkyl, C₃₋₈heterocycloalkyl, C₃₋₈ cycloalkenyl, C₃₋₈ heterocycloalkenyl, aryl orheteroaryl moiety, wherein the aryl or heteroaryl moiety either contains5 or 6 atoms in a single ring or from 7 to 14 atoms in a fusedpolycyclic ring system, wherein, when substituted, R¹ contains from 1 to9 substituents independently selected at each occurrence from the groupcomprising: halo, —OR^(f), —NR^(f)R^(g), ═O, —CN, acyl, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkyl substituted with —OR^(f), C₁₋₆ alkyl substitutedwith C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl, —SO₂R^(f),SO₃R^(f), —C(O)R^(f), —C(O)OR^(f), C(O)NR^(f)R^(g), aryl optionallysubstituted by 1 or 2 halo atoms, and 6 membered heteroaryl; R² isselected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, and C₃₋₇halocycloalkyl; R³ and R⁴ are independently selected at each occurrencefrom: H, halo, C₁₋₄ alkyl, C₁₋₄ alkyl substituted with —OR^(h), C₁₋₄haloalkyl, C₃₋₆ cycloalkyl and C₃₋₇ halocycloalkyl, or R³ and R⁴ takentogether with the atom on which they are substituted, form a 3 to 6membered cycloalkyl ring; R⁵ and R⁶ are independently selected at eachoccurrence from: H, C₁₋₄ alkyl, C₁₋₄ alkyl substituted with —OR^(h),C₁₋₄ haloalkyl, C₁₋₄ acyl, C₃₋₇ cycloalkyl, and C₃₋₇ halocycloalkyl;R^(a) and R^(b) are independently selected at each occurrence from: H,C₁₋₄ alkyl, C₁₋₄ alkyl substituted with —OR^(i), C₁₋₄ haloalkyl, acyl,C₃₋₇ cycloalkyl, and C₃₋₇ halocycloalkyl; R^(c), R^(d) and R^(e) areindependently selected at each occurrence from: H, C₁₋₄ haloalkyl, C₁₋₄alkyl substituted with —OR^(j), unsubstituted aryl, aryl substitutedwith halo or C₁₋₄ alkyl or C₁₋₄ haloalkyl or a combination thereof, C₃₋₇cycloalkyl, and C₃₋₇ halocycloalkyl; R^(f) and R^(g) are independentlyselected at each occurrence from: H, C₁₋₄ alkyl, C₁₋₄ alkyl substitutedwith —OR^(k), C₁₋₄ haloalkyl, acyl, C₃₋₇ cycloalkyl, and C₃₋₇halocycloalkyl; R^(h), R^(i), and R^(k) are independently selected ateach occurrence from: C₁₋₄ alkyl, C₁₋₄ alkyl substituted with —OR^(l)and C₁₋₄ haloalkyl; and R¹ is independently selected at each occurrencefrom: H, C₁₋₄ alkyl, and C₁₋₄ haloalkyl.
 2. A compound of claim 1,wherein at least one of the 1 to 9 substituents on R¹ and the —C(═O)—group are bonded to adjacent carbon atoms of R¹.
 3. A compound of claim1, wherein R¹ is selected from H, C₁₋₄ alkyl, and C₃₋₇ cycloalkyl.
 4. Acompound of claim 1, wherein R³ and R⁴ are independently selected ateach occurrence from: H, fluoro, chloro, methyl, ethyl, trifluoromethyl,trifluoroethyl, methoxy, ethoxy, OCF₃, —CH₂OH or R³ and R⁴ takentogether with the atom on which they are substituted form a cyclopropylring.
 5. A compound of claim 1, wherein n is
 1. 6. A compound claim 1,wherein X is N and Y is C.
 7. A compound of claim 1, wherein X is C andY is N.
 8. A compound of claim 1, wherein A is substituted orunsubstituted phenyl.
 9. A compound of claim 1, wherein A is substitutedby

which are substituted ortho to one another on A.
 10. A compound of claim1, wherein R¹ is substituted or unsubstituted 6 membered aryl or 6membered heteroaryl, optionally unsubstituted phenyl, unsubstitutedpyridyl, substituted pyridyl or substituted phenyl.
 11. A compound ofclaim 1, wherein R¹ is a substituted or unsubstituted: C₃₋₈ cycloalkyl,C₃₋₈ heterocycloalkyl, C₃₋₈ cycloalkenyl, C₃₋₈ heterocycloalkenyl, arylor heteroaryl moiety, wherein the aryl or heteroaryl moiety eithercontains 5 or 6 atoms in a single ring or from 7 to 14 atoms in a fusedpolycyclic ring system, and wherein the —C(═O)— and one of thesubstituents on the C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl, C₃₋₈cycloalkenyl or C₃₋₈ heterocycloalkenyl moiety or the aryl or heteroarylsingle ring are bonded to adjacent carbon atoms of R¹ or, wherein thearyl or heteroaryl moiety contains from 7 to 14 atoms in a fusedpolycyclic ring system, the —C(═O)— group is substituted on the aryl orheteroaryl fused polycyclic ring system ortho to one of the two pointsof fusion of the polycyclic system.
 12. A compound of claim 1, wherein Dis selected from substituted or unsubstituted: tert-butyl,trifluoromethyl, cyclopentyl, cyclohexyl, bicyclohexyl, cyclopentenyl,cyclohexenyl, indanyl, tetrahydrofuran and tetrahydropyran.
 13. Acompound of claim 1, wherein: X is C, Y is N; and D is selected fromsubstituted or unsubstituted: C₁₋₆ alkyl, C₃₋₁₀ cycloalkenyl, C₆₋₁₀aryl, 3 to 10 membered heterocycloalkyl, 3 to 10 memberedheterocycloalkenyl and 5 to 10 membered heteroaryl, substituted C₃₋₁₀cycloalkyl, unsubstituted C₃₋₄ cycloalkyl or unsubstituted C₆₋₁₀cycloalkyl, and R¹ is a group selected from a substituted orunsubstituted: C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl, C₃₋₈cycloalkenyl, C₃₋₈ heterocycloalkenyl, aryl or heteroaryl moiety,wherein the aryl or heteroaryl moiety either contains 5 or 6 atoms in asingle ring or from 7 to 14 atoms in a fused polycyclic ring system; orD is unsubstituted cyclopentyl and R¹ is a substituted or unsubstituted:C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl, C₃₋₈ cycloalkenyl, C₃₋₈heterocycloalkenyl, aryl or heteroaryl moiety, wherein the aryl orheteroaryl moiety either contains 5 or 6 atoms in a single ring or from7 to 14 atoms in a fused polycyclic ring system, wherein the —C(═O)— andone of the substituents on the C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl,C₃₋₈ cycloalkenyl or C₃₋₈ heterocycloalkenyl moiety or the aryl orheteroaryl single ring are bonded to adjacent carbon atoms of R¹ and the—C(═O)— group is substituted on the aryl or heteroaryl fused polycyclicring system ortho to one of the two points of fusion of the polycyclicsystem; or X is N, Y is C; D is selected from substituted orunsubstituted: C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkenyl, C₆₋₁₀aryl, 3 to 10 membered heterocycloalkyl, 3 to 10 memberedheterocycloalkenyl and 5 to 10 membered heteroaryl; and R¹ is a groupselected from a substituted or unsubstituted: C₃₋₈ cycloalkyl, C₃₋₈heterocycloalkyl, C₃₋₈ cycloalkenyl, C₃₋₈ heterocycloalkenyl, aryl orheteroaryl moiety, wherein the aryl or heteroaryl moiety either contains5 or 6 atoms in a single ring or from 7 to 14 atoms in a fusedpolycyclic ring system.
 14. A compound of claim 1, wherein the compoundof formula (I) is a compound selected from:

or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition, wherein the pharmaceutical composition comprises a compoundof claim 1, or a pharmaceutically acceptable salt thereof, andpharmaceutically acceptable excipients.
 16. A pharmaceutical compositionof claim 15, wherein the composition is a combination product andcomprises an additional pharmaceutically active agent.
 17. A method oftreatment of a condition which is modulated by Bruton's tyrosine kinase,wherein the method comprises administering a therapeutic amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof, to apatient in need thereof.
 18. A method of claim 17 wherein the conditionmodulated by BTK is cancer, lymphoma, leukemia, immunological disease,autoimmune diseases and inflammatory disorders.